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Physics-based scoring function AutoDock4 is one of the most successfully applied tools in the area of structure-based drug design. However, current scoring functions are still far from being perfect. In a recent work highlighting the strengths and deficiencies of current scoring functions, we discovered that the residual error of ΔG bind predictions made by AutoDock4 is highly correlated to the presence of formally charged fragments in a ligand. In this work, we study how the use of the high-quality atomic charges, applied for contemporary force fields calculation, affects the quality of the experimental ΔG bind prediction by means of AutoDock4. We initially expected that the previously found discrepancy could be attributed to the Gasteiger charges used within AutoDock4. We show that AutoDock4 is, surprisingly, not sensitive to the charges used, and the use of QC-derived atomic charges does not lead to any statistical improvements. We also briefly discuss the role of the explicit empirical hydrogen bond term along with the electrostatic term., (© 2024 Wiley Periodicals LLC.)

During the first years of COVID-19 pandemic, X-ray structures of the coronavirus drug targets were acquired at an unprecedented rate, giving hundreds of PDB depositions in less than a year. The main protease (Mpro) of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is the primary validated target of direct-acting antivirals. The selection of the optimal ensemble of structures of Mpro for the docking-driven virtual screening campaign was thus non-trivial and required a systematic and automated approach. Here we report a semi-automated active site RMSD based procedure of ensemble selection from the SARS-CoV-2 Mpro crystallographic data and virtual screening of its inhibitors. The procedure was compared with other approaches to ensemble selection and validated with the help of hand-picked and peer-reviewed activity-annotated libraries. Prospective virtual screening of non-covalent Mpro inhibitors resulted in a new chemotype of thienopyrimidinone derivatives with experimentally confirmed enzyme inhibition., (© 2024 Wiley-VCH GmbH.)

The emergence of new drug-resistant strains of the tuberculosis pathogen Mycobacterium tuberculosis (Mtb) is a new challenge for modern medicine. Its resistance capacity is closely related to the properties of the outer membrane of the Mtb cell wall, which is a bilayer membrane formed by mycolic acids (MAs) and their derivatives. To date, the molecular mechanisms of the response of the Mtb outer membrane to external factors and, in particular, elevated temperatures have not been sufficiently studied. In this work, we consider the temperature-induced changes in the structure, ordering, and molecular mobility of bilayer MA membranes of various chemical and conformational compositions. Using all-atom long-term molecular dynamics simulations of various MA membranes, we report the kinetic parameters of temperature-dependent changes in the MA self-diffusion coefficients and conformational compositions, including the apparent activation energies of these processes, as well as the characteristic times of ordering changes and the features of phase transitions occurring over a wide range of elevated temperatures. Understanding these effects could be useful for the prevention of drug resistance and the development of membrane-targeting pharmaceuticals, as well as in the design of membrane-based materials.

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6-13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37-63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC 50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d : IC 50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β -amyloid (A β ) aggregation. Hybrids also exhibited the inhibition of A β self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.

An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent S N Ar reactions of 5-nitroisoxazoles with various O , O -, N , N - and S , S -bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5'-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10 -12 -10 -6 M) with maximum potentiation of 77% at 10 -10 M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs.

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ 42 ) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC 50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d , an analog of dihydroacridine, 1d , was an effective BChE inhibitor (IC 50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ 42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS •+ -scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ 42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations., Competing Interests: RR currently serves as a member of the advisory board of NeuroX1, a startup biotechnology company that is developing a software platform for the discovery and development of drugs for neurodegenerative diseases. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.)

The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1 3,11 ]tetradecane-4,8,12-trione-had been developed and all steps of synthesis were optimized. The structures of the compounds contain tricyclic cage and indane fragments necessary for binding with the target receptor. Their physiological activity was studied by radioligand-receptor binding analysis using [ 3 H]PAM-43 as a reference ligand, which is a highly potent positive allosteric modulator of AMPA receptors. The results of radioligand-binding studies indicated the high potency of two synthesized compounds to bind with the same targets as positive allosteric modulator PAM-43 (at least on AMPA receptors). We suggest that the Glu-dependent specific binding site of [ 3 H]PAM-43 or the receptor containing this site may be one of the targets of the new compounds. We also suggest that enhanced radioligand binding may indicate the existence of synergistic effects of compounds 11b and 11c with respect to PAM-43 binding to the targets. At the same time, these compounds may not compete directly with PAM-43 for its specific binding sites but bind to other specific sites of this biotarget, changing its conformation and thereby causing a synergistic effect of cooperative interaction. It can be expected that the newly synthesized compounds will also have pronounced effects on the glutamatergic system of the mammalian brain.

The proper and precise reproduction of the molecular electrostatic potential (MEP) is crucial to describe correctly electrostatic interactions in molecular modeling. Most of the classical molecular mechanics force fields for biomolecules and drug-like molecules use the atom-centered point charges to describe MEP. However, it has been systematically pointed out in literature that such an approximation is not always enough, and some groups, like amino group or heavy halogens, require the use of anisotropic model for better description of their MEP. At the same time, the formally charged groups have not been as extensively and systematically studied as their neutral counterparts. In this report, we demonstrate that the anisotropic models for formally charged groups do bring improvements in the reference MEP reproduction, that are comparable in magnitude to those for neutral groups., (© 2023 Wiley Periodicals LLC.)

Introduction of point mutations is one of the forces enabling arboviruses to rapidly adapt in a changing environment. The influence of these mutations on the properties of the virus is not always obvious. In this study, we attempted to clarify this influence using an in silico approach. Using molecular dynamics (MD) simulations, we investigated how the position of charge-changing point mutations influences the structure and conformational stability of the E protein for a set of variants of a single TBEV strain. The computational findings were supported by experimental evaluation of relevant properties of virions, such as binding to heparan sulfate, thermostability, and susceptibility of the viral hemagglutinating activity to detergents. Our results also point to relationships between E protein dynamics and viral neuroinvasiveness., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC 50 values of the lead compound 10c were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced β -amyloid aggregation. All conjugates inhibited Aβ 42 self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine 10c and salicylamide 5c with (CH 2 ) 8 spacers were the lead compounds for inhibiting Aβ 42 self-aggregation, which was corroborated by molecular docking to Aβ 42 . ABTS •+ -scavenging activity was highest for salicylamides 5a-c , intermediate for salicylimines 10a-c , low for F-containing salicylamides 7 , and non-existent for methoxybenzoylamides 6 and difluoromethoxybenzoylamides 8 . In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu 2+ , Fe 2+ , and Zn 2+ , with molar compound/metal (Cu 2+ ) ratios of 2:1 ( 5b ) and ~1:1 ( 10b ). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.

The cell wall of Mycobacterium tuberculosis and related organisms has a very complex and unusual organization that makes it much less permeable to nutrients and antibiotics, leading to the low activity of many potential antimycobacterial drugs against whole-cell mycobacteria compared to their isolated molecular biotargets. The ability to predict and optimize the cell wall permeability could greatly enhance the development of novel antitubercular agents. Using an extensive structure-permeability dataset for organic compounds derived from published experimental big data (5371 compounds including 2671 penetrating and 2700 non-penetrating compounds), we have created a predictive classification model based on fragmental descriptors and an artificial neural network of a novel architecture that provides better accuracy (cross-validated balanced accuracy 0.768, sensitivity 0.768, specificity 0.769, area under ROC curve 0.911) and applicability domain compared with the previously published results.

Amphipathic nucleoside and non-nucleoside derivatives of pentacyclic aromatic hydrocarbon perylene are known as potent non-cytotoxic broad-spectrum antivirals. Here we report 3-methyl-5-(perylen-3-ylethynyl)-uracil-1-acetic acid and its amides, a new series of compounds based on a 5-(perylen-3-ylethynyl)-uracil scaffold. The compounds demonstrate pronounced in vitro activity against arthropod-borne viruses, namely tick-borne encephalitis virus (TBEV) and yellow fever virus (YFV), in plaque reduction assays with EC 50 values below 1.9 and 1.3 nM, respectively, and Chikungunya virus (CHIKV) in cytopathic effect inhibition test with EC 50 values below 3.2 μM. The compounds are active against respiratory viruses as well: severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in cytopathic effect inhibition test and influenza A virus (IAV) in virus titer reduction experiments are inhibited - EC 50 values below 51 nM and 2.2 μM, respectively. The activity stems from the presence of a hydrophobic perylene core, and all of the synthesized compounds exhibit comparable 1 O 2 generation rates. Nonetheless, activity can vary by orders of magnitude depending on the hydrophilic part of the molecule, suggesting a complex mode of action. A time-of-addition experiment and fluorescent imaging indicate that the compounds inhibit viral fusion in a dose-dependent manner. The localization of the compound in the lipid bilayers and visible damage to the viral envelope suggest the membrane as the primary target. Dramatic reduction of antiviral activity with limited irradiation or under treatment with antioxidants further cements the idea of photoinduced ROS-mediated viral envelope damage being the mode of antiviral action., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

L-Glutamic acid is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors localized on neuronal and non-neuronal cells mediate rapid excitatory synaptic transmission in the CNS and regulate a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. In particular, the glutamate receptors selective to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also play an important role in numerous neurological disorders and attract close attention as targets for the creation of new classes of drugs for the treatment or substantial correction of a number of serious neurodegenerative and neuropsychiatric diseases. For this reason, the search for various types of AMPA receptor ligands and studies of their properties are attracting considerable attention both in academic institutions and in pharmaceutical companies around the world. This review focuses mainly on the advances in this area published since 2017. Particular attention is paid to the structural diversity of new chemotypes of agonists, competitive AMPA receptor antagonists, positive and negative allosteric modulators, transmembrane AMPA regulatory protein (TARP) dependent allosteric modulators, ion channel blockers as well as their binding sites. This review also presents the studies of the mechanisms of action of AMPA receptor ligands that mediate their therapeutic effects.

Scoring functions (SFs) are ubiquitous tools for early stage drug discovery. However, their accuracy currently remains quite moderate. Despite a number of successful target-specific SFs appearing recently, up until now, no ideas on how to systematically improve the general scope of SFs have been formulated. In this work, we hypothesized that the specific features of ligands, corresponding to interactions well appreciated by medicinal chemists (e.g., hydrogen bonds, hydrophobic and aromatic interactions), might be responsible, in part, for the remaining SF errors. The latter provides direction to efforts aimed at the rational and systematic improvement of SF accuracy. In this proof-of-concept work, we took a CASF-2016 coreset of 285 ligands as a basis for comparison and calculated the values of scores for a representative panel of SFs (including AutoDock 4.2, AutoDock Vina, X-Score, NNScore2.0, ΔVina RF20, and DSX). The residual error of linear correlation of each SF value, with the experimental values of affinity and activity, was then analyzed in terms of its correlation with the presence of the fragments responsible for certain medicinal chemistry defined interactions. We showed that, despite the fact that SFs generally perform reasonably, there is room for improvement in terms of better parameterization of interactions involving certain fragments in ligands. Thus, this approach opens a potential way for the systematic improvement of SFs without their significant complication. However, the straightforward application of the proposed approach is limited by the scarcity of reliable available data for ligand-receptor complexes, which is a common problem in the field.

Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor's allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5 H -cyclohepta[ d ]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10 -12 -10 -6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

A series of new 1,2,4-triazolo-linked bis -indolyl conjugates ( 15a-r ) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC 50 = 2.04 μM) and 15r (IC 50 = 0.85 μM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC 50 = 5.31 μM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G 0 /G 1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 μM and 1 μM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, β-catenin, TAB-182, β-actin, AXIN-2, and NF-κB markers that are involved in the β-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors ( 15r ) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.

Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC 50 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC 50 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu 2+ , Fe 2+ , and Zn 2+ , as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe 3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development., Competing Interests: The authors declare no conflicts of interest.

Polarization and inductive effects are the concepts that have been widely used in qualitative and even quantitative descriptions of experimentally observed properties in chemistry. The polarization effect has proven to be important in cases of biomolecular modeling though still the vast majority of molecular simulations use the classical non-polarizable force fields. In the last few decades, a lot of effort has been put into promoting the polarization effect and incorporating it into modern force fields and charge calculation methods. In contrast, the inductive effect has not attracted such attention and is effectively absent in both classic and modern force fields. Thus, a question is whether this difference corresponds to the difference in the physical significance of the effects and their explicit account, or is an artifact that should be corrected in the next generation of force fields. The significance of the electronic effects is studied in this paper through the prism of performance of specific models for atomic charge calculation that take into explicit account a nested set of effects: the formal charge, the nearest neighbors, the inductive effect, and finally the model, which takes into account all effects, which are possible to account for using atomic charges. The specific choice for the methods is the following: formal charges, MMFF94 bond charge increments, Dynamic Electronegativity Relaxation (DENR), and RESP. We propose a special scheme for the separate estimation of each particular effect contribution. By pairwise comparing the residual molecular electrostatic potential (MEP) errors of those charge models (aimed at best reproducing the quantum chemical reference MEP), we sequentially revealed how the account of each effect contributes to the better-quality MEP reproduction. The following relative importance of effects was estimated; thus, the natural hierarchy of the effects was established. First, the account of formal charges is of primordial importance. Second, the nearest neighbors account is the next in significance. Third, the explicit account of inductive effect in empirical charge calculation schemes was shown to significantly─both qualitatively and quantitatively─improve the quality of MEP reproduction. Fourth, the contribution of polarization is indirectly assessed. Surprisingly, it is of the order of magnitude of the inductive effect even for the molecular systems, for which it is anticipated to be more significant. Finally, the relative importance of anisotropic effects in neutral molecules was additionally reviewed.

NMDA ( N -methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC 50 = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

A series of novel antimitotic agents was designed using the replacement of heterocyclic cores in two tubulin-targeting lead molecules with the acylated 4-aminoisoxazole moiety. Target compounds were synthesized via heterocyclization of β-aryl-substituted vinylketones by tert-butyl nitrite in the presence of water as a key step. 4-Methyl-N-[5-methyl-3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]benzamide (1aa) was found to stimulate partial depolymerization of microtubules of human lung carcinoma A549 cells at a high concentration of 100 µM and to totally inhibit cell growth (IC 50  = 0.99 µM) and cell viability (IC 50  = 0.271 µM) in the nanomolar to submicromolar concentration range. These data provide evidence of the multitarget profile of the cytotoxic action of compound 1aa. The SAR study demonstrated that the 3,4,5-trimethoxyphenyl residue is the key structural parameter determining the efficiency both towards tubulin and other molecular targets. The cytotoxicity of 3-methyl-N-[5-methyl-3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl]benzamide (1ab) to the androgen-sensitive human prostate adenocarcinoma cancer cell line LNCaP (IC 50  = 0.301 µM) was approximately one order of magnitude higher than that to the conditionally normal cells lines WI-26 VA4 (IC 50  = 2.26 µM) and human umbilical vein endothelial cells (IC 50  = 5.58 µM) and significantly higher than that to primary fibroblasts (IC 50  > 75 µM)., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

The notion of a contribution of a specific group in an organic molecule's property and/or activity is both common in our thinking and is still not strictly correct due to the inherent non-additivity of free energy with respect to molecular fragments composing a molecule. The fragment- based drug discovery (FBDD) approach has proven to be fruitful in addressing the above notions. The main difficulty of the FBDD, however, is in its reliance on the low throughput and expensive experimental means of determining the fragment-sized molecules binding. In this article we propose a way to enhance the throughput and availability of the FBDD methods by judiciously using an in silico means of assessing the contribution to ligand-receptor binding energy of fragments of a molecule under question using a previously developed in silico Reverse Fragment Based Drug Discovery (R-FBDD) approach. It has been shown that the proposed structure-based drug discovery (SBDD) type of approach fills in the vacant niche among the existing in silico approaches, which mainly stem from the ligand-based drug discovery (LBDD) counterparts. In order to illustrate the applicability of the approach, our work retrospectively repeats the findings of the use case of an FBDD hit-to-lead project devoted to the experimentally based determination of additive group efficiency (GE)-an analog of ligand efficiency (LE) for a group in the molecule-using the Free-Wilson (FW) decomposition. It is shown that in using our in silico approach to evaluate fragment contributions of a ligand and to estimate GE one can arrive at similar decisions as those made using the experimentally determined activity-based FW decomposition. It is also shown that the approach is rather robust to the choice of the scoring function, provided the latter demonstrates a decent scoring power. We argue that the proposed approach of in silico assessment of GE has a wider applicability domain and expect that it will be widely applicable to enhance the net throughput of drug discovery based on the FBDD paradigm.

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis- N -acyl-alkylene ( 3 ) and bis- N -thiourea-alkylene ( 5 ) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis- N -acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a -c exhibited an IC 50 (AChE) = 2.9-1.4 µM, IC 50 (BChE) = 0.13-0.067 µM, and 14-18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ 42 aggregation. Conjugates 3 had no effect on Aβ 42 self-aggregation, whereas compounds 5c - e ( m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N -acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled ( 5 ) or exceeded ( 3 ) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c - e appear promising for future optimization and development as multitarget anti-AD agents.

A convenient synthetic approach to novel functionalized bis(isoxazoles), the promising bivalent ligands of the AMPA receptor, was elaborated. It was based on the heterocyclization reactions of readily available electrophilic alkenes with the tetranitromethane-triethylamine complex. The structural diversity of the synthesized compounds was demonstrated. In the electrophysiological experiments using the patch clamp technique on Purkinje neurons, the compound 1,4-phenylenedi(methylene)bis(5-aminoisoxazole-3-carboxylate) was shown to be highly potent positive modulator of the AMPA receptor, potentiating kainate-induced currents up to 70% at 10 -11 M.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC 50 for AChE = 1.83 ± 0.03 μM (K i  = 1.50 ± 0.12 and αK i  = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pK a values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc) 2 -catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, bind to the CES active site suggesting subsequent reactions: formation of a tetrahedral adduct, and a slow hydrolysis reaction. The results of molecular modeling allowed us to explain some structure-activity relationships of CES inhibition by HOPs 3: their selectivity toward CES in comparison with cholinesterases and the high selectivity of pentafluoroethyl-substituted HOP 3p to hCES1 compared to hCES2. All compounds were predicted to have good intestinal absorption and blood-brain barrier permeability, low cardiac toxicity, good lipophilicity and aqueous solubility, and reasonable overall drug-likeness. HOPs with a TFK group and electron-donor substituents in the arylhydrazone moiety were potent antioxidants. All compounds possessed low cytotoxicity and low acute toxicity. Overall, a new promising type of bifunctional CES inhibitors has been found that are able to interact with the active site of the enzyme with the participation of two functional groups. The results indicate that HOPs have the potential to be good candidates as human CES inhibitors for biomedicinal applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

3,7-Diazabicyclo[3.3.1]nonane scaffold can serve as a basis for the design of molecular switches stimulating the fast release of water soluble compounds under the influence of external factors from the liposomal containers having those switches incorporated into the lipid bilayer. It was demonstrated that liposomes having 3,7-dihexadecyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one (3) incorporated into the liposomal membrane sharply increase the permeability upon pH decrease from 7.4 to 6.5, and compound 3 can serve as a pH-sensitive agent in the bilayer of liposomal nanocontainers. Similar but less pronounced effect was shown for liposomes modified with 3,7-bis(methyldodecylaminoacetyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane (5) and 3,7-didodecylsulfonyl-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one (4). The structure (morphology) and size of modified liposomes were studied with scanned transmission electron microscopy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. This review mainly focuses on recent advances in this field. The architecture and operational mechanism of the receptor as well as its major binding sites and ligand types are considered. Special attention is paid to the studies of mechanisms of action and novel chemotypes of AMPA receptor agonists and competitive antagonists, positive and negative allosteric modulators, auxiliary protein-dependent allosteric modulators, and ion channel blockers.

Permeation through the blood-brain barrier (BBB) is among the most important processes controlling the pharmacokinetic properties of drugs and other bioactive compounds. Using the fragmental (substructural) descriptors representing the occurrence number of various substructures, as well as the artificial neural network approach and the double cross-validation procedure, we have developed a predictive in silico LogBB model based on an extensive and verified dataset (529 compounds), which is applicable to diverse drugs and drug-like compounds. The model has good predictivity parameters (Q2=0.815, RMSEcv=0.318) that are similar to or better than those of the most reliable models available in the literature. Larger datasets, and perhaps more sophisticated network architectures, are required to realize the full potential of deep neural networks. The analysis of fragment contributions reveals patterns of influence consistent with the known concepts of structural characteristics that affect the BBB permeability of organic compounds. The external validation of the model confirms good agreement between the predicted and experimental LogBB values for most of the compounds. The model enables the evaluation and optimization of the BBB permeability of potential neuroactive agents and other drug compounds.

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl ( 7 ) or aminoalkyl ( 8 ) spacers were synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c , 2,6-di- tert -butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC 50 (AChE) = 1.90 ± 0.16 µM, IC 50 (BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7 . Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p -tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer's disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide ( 7h ) exhibited an IC 50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC 50 (BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC 50 values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

Background: Currently, the most dynamic areas in the glutamate receptor system neurobiology are the identification and development of positive allosteric modulators (PAMs) of glutamate ionotropic receptors. PAM-based drugs are of great interest as promising candidates for the treatment of neurological diseases, such as epilepsy, Alzheimer's disease, schizophrenia, etc. Understanding the molecular mechanisms underlying the biological action of natural and synthetic PAMs is a key point for modifying the original chemical compounds as well as for new drug design., Objective: We are trying to elaborate a system of molecular functional screening of ionotropic glutamate receptor probable PAMs., Methods: The system will be based on the radioligand - receptor method of analysis and will allow rapid quantification of new AMPAR probable PAMs molecular activity. We plan to use a tritiumlabeled analogue of recently elaborated ionotropic GluR probable PAM ([3H]PAM-43) as the main radioligand., Results: Here, we characterized the specific binding of the ligand and its ability to potentiate ionotropic GluR currents. The existence of at least two different sites of [3H]PAM-43 specific binding has been shown. One of the above sites is glutamate-dependent and is characterized by higher affinity. "Patchclamp" technique showed the ability of PAM-43 to potentiate ionotropic GluR currents in rat cerebellar Purkinje neurons in a concentration-dependent manner., Conclusion: The possibility of using PAM-43 as a model compound to study different allosteric effects of potential regulatory drugs (AMPAR allosteric regulators) was shown. [3H]PAM-43 based screening system will allow rapid selection of new AMPAR probable PAM structures and quantification of their molecular activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tick-borne encephalitis is an important human arbovirus neuroinfection spread across the Northern Eurasia. Inhibitors of tick-borne encephalitis virus (TBEV) strain Absettarov, presumably targeting E protein n -octyl-β-d-glucoside (β-OG) pocket, were reported earlier. In this work, these inhibitors were tested in vitro against seven strains representing three main TBEV subtypes. The most potent compound, 2-[(2-methyl-1-oxido-5,6,7,8-tetrahydroquinazolin-4-yl)amino]-phenol, showed EC 50 values lower than 22 µM against all the tested strains. Nevertheless, EC 50 values for virus samples of certain strains demonstrated a substantial variation, which appeared to be consistent with the presence of E protein not only in infectious virions, but also in non-infectious and immature virus particles, protein aggregates, and membrane complexes.

We synthesized conjugates of tacrine with 1,2,4-thiadiazole derivatives linked by two different spacers, pentylaminopropene (compounds 4) and pentylaminopropane (compounds 5), as potential drugs for the treatment of Alzheimer's disease (AD). The conjugates effectively inhibited cholinesterases with a predominant effect on butyrylcholinesterase (BChE). They were also effective at displacing propidium from the peripheral anionic site (PAS) of acetylcholinesterase (AChE), suggesting that they could block AChE-induced β-amyloid aggregation. In addition, the compounds exhibited high radical-scavenging capacity. Conjugates 5 had higher anti-BChE activity and greater anti-aggregant potential as well relatively lower potency against carboxylesterase than compounds 4. Quantum-mechanical (QM) characterization agreed with NMR data to identify the most stable forms of conjugates for docking studies, which showed that the compounds bind to both CAS and PAS of AChE consistent with mixed reversible inhibition. Conjugates 4 were more potent radical scavengers, in agreement with HOMO localization in the enamine-thiadiazole system. Computational studies showed that all of the conjugates were expected to have good intestinal absorption, whereas conjugates 4 and 5 were predicted to have medium and high blood-brain barrier permeability, respectively. All conjugates were predicted to have medium cardiac toxicity risks. Overall, the results indicated that the conjugates are promising candidates for further development and optimization as multifunctional therapeutic agents for the treatment of AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of new positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors based on 3,7-diazabicyclo[3.3.1]nonane scaffold have been designed, synthesized, and analyzed. In electrophysiological patch clamp studies, several compounds have demonstrated a sub-nanomolar potency. Compound 4 in in vivo tests showed anti-amnestic properties in the scopolamine-induced model of amnesia in the step-through passive avoidance or maximal electroshock experiments in rats at 0.01 mg/kg showing a significant "dose-response" advantage over memantine. Based on the analysis of the flexible docking results of PAMs, the cyclothiazide-like mechanism of binding mode was suggested as the major site for the interaction with AMPA receptors.