Search

Background: Despite tremendous efforts made by scientific community during the outbreak of COVID‐19 pandemic, this disease still remains as a public health concern. Although different types of vaccines were globally used to reduce the mortality, emergence of new variants of SARS‐CoV‐2 is a challenging issue in COVID‐19 pharmacotherapy. In this context, target therapy of SARS‐CoV‐2 by small ligands is a promising strategy. Methods: In this investigation, we applied ligand‐based virtual screening for finding novel molecules based on nirmatrelvir structure. Various criteria including drug‐likeness, ADME, and toxicity properties were applied for filtering the compounds. The selected candidate molecules were subjected to molecular docking and dynamics simulation for predicting the binding mode and binding free energy, respectively. Then the molecules were experimentally evaluated in terms of antiviral activity against SARS‐CoV‐2 and toxicity assessment. Results: The results demonstrated that the identified compounds showed inhibitory activity towards SARS‐CoV‐2 Mpro. Conclusion: In summary, the introduced compounds may provide novel scaffold for further structural modification and optimization with improved anti SARS‐CoV‐2 Mpro activity. [ABSTRACT FROM AUTHOR]

Recently, multi‐target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual‐acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6‐chloro‐N‐methyl‐N‐[3‐(4‐methylpiperazin‐1‐yl)propyl]‐1H‐indole‐2‐carboxamide) and compound 4 (7‐chloro‐N‐[(1‐methylpiperidin‐3‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinoline‐2‐carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy. [ABSTRACT FROM AUTHOR]

Histamine H3 receptors (H3R), belonging to G‐protein coupled receptors (GPCR) class A superfamily, are responsible for modulating the release of histamine as well as of other neurotransmitters by a negative feedback mechanism mainly in the central nervous system (CNS). These receptors have gained increased attention as therapeutic target for several CNS related neurological diseases. In the current study, we aimed to identify novel H3R ligands using in silico virtual screening methods. To this end, a combination of ligand‐ and structure‐based approaches was utilized for screening of ZINC database on the homology model of human H3R. Structural similarity‐ and pharmacophore‐based approaches were employed to generate compound libraries. Various molecular modeling methodologies such as molecular docking and dynamics simulation along with different drug likeness filtering criteria were applied to select anti‐H3R ligands as promising candidate molecules based on different known parent lead compounds. In vitro binding assays of the selected molecules demonstrated three of them being active within the micromolar and submicromolar Ki range. The current integrated computational and experimental methods used in this work can provide new general insights for systematic hit identification for novel anti‐H3R agents from large compound libraries. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine which plays crucial roles in pathogenesis of inflammatory diseases. The current study aimed to investigate the binding abilities of I44 and I49 domain antibodies to TNF-α. The dAbs were expressed in bacterial expression system and purified by affinity chromatography using Ni-sepharose column. The expression and purity of the proteins were evaluated using western blotting and SDS-PAGE techniques, respectively. ELISA experiment showed that I44 and I49 dAbs bind to TNF-α with the binding constants (Kd) of 5.18 ± 1.41 and 2.42 ± 0.55 μM, respectively. The inhibitory effect of dAbs on TNF-α biological effect was determined in MTT assay in which I44 and I49 prevented TNF-α cell cytotoxicity with IC50 values of 6.61 and 3.64 μM, respectively. The identified anti-TNF-α dAbs could bind to and inhibit TNF-α activity. The dAbs activities can be attributed to their ability to establish hydrogen bonds as well as hydrophobic contacts with TNF-α. The results of the current study can pave the way for further structural studies in order to introduce new more potent anti-TNF-α antibodies. [ABSTRACT FROM AUTHOR]

Single-chain fragment variable (scFv) antibodies are antibody fragments consist of variable domains of full antibodies known to retain antigen binding properties while having much lower molecular weights granting some beneficial properties to them. In our previous study, three phage particles each displaying an individual scFv antibody (i.e. J43, J44, and J48) were identified as tumor necrosis factor alpha (TNF-α) binders. The current study aimed to produce previously identified anti-TNF-α scFv antibodies and to investigate their abilities to bind and inhibit TNF-α biological effect. The estimated free energy of folding determined using spectrofluorimetry method for the prepared scFv proteins was in the range of 6.35-12.45 kJ mol−1 indicating their proper folding in the solution. In ELISA experiment, the produced scFvs showed an appropriate affinity towards TNF-α with Kd values in the range of 0.5-2.18 µM. They also inhibited the TNF-α-induced cytotoxicity on L929 cells with sub-micromolar IC50 values (0.12 and 0.73 μM for J44 and J48, respectively). Molecular docking studies showed that J44 could mimic adalimumab interactions with TNF-α, confirming its relatively high TNF-α inhibitory effect compared to J43 and J48. It seems that the findings in the current study can be useful for designing more potent anti-TNF-α antibodies. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify novel TNF-α blocking peptide(s) using phage display technology. Two novel 7-mer TNF-α binding peptides P51 and P52 with K d values of 1.47 and 0.51 nM were identified. Phage particles displaying P51 and P52 peptides at 0.318 nM concentration prevent cytotoxic effect of TNF-α on L929 cells by 8.2% and 16.15%, respectively. Synthesized P51 and P52 peptides also inhibited TNF-α induced cytotoxicity with IC 50 values of 25.15 ± 2.18 and 7.08 ± 2.24 μM, respectively. The result of RT-PCR also supports the inhibitory activity of the identified peptides, where P51 and P52 significantly inhibit the inductive effect of TNF-α on IκB-α mRNA levels. The inhibitory effects of the peptides were attributed to their abilities of binding at the inter-subunit interfaces leading to TNF-α dissociation. The results of molecular docking studies revealed that the peptides-TNF-α complexes are mostly stabilized by hydrophobic contacts. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a disease caused by a protozoan parasites belonging to the genus Leishmania. It causes morbidity and mortality in the tropical and subtropical regions. Current drugs are toxic, expensive, and require long-term treatment. Thus, identification and development of novel, cheap, efficient, and safe antileishmanial compounds as drug candidates are important from pharmaceutical point of view. Quantitative structure-activity relationship (QSAR) methods are used to predict the pharmaceutically relevant properties of drug candidates whenever it is applicable. The aim of this study was to use two different techniques, namely multiple linear regression (MLR) and artificial neural networks (ANNs) in predicting the antileishmanial activity (i.e. pIC50) of 5-(5-nitroheteroaryl-2-y1)-1,3,4-thiadiazole derivatives. To this end, genetic algorithm-coupled partial least square and backward multiple regression method were used to select a number of calculated molecular descriptors to be used in MLR and ANN-based QSAR studies. The predictive power of the models was also assessed using leave-one-out and leave-group-out cross validation methods. Also, molecular modeling studies were conducted based on DNA topoisomerase I to identify the binding interactions responsible for antileishmanial activity of those analogs. The results suggest that hydrogen bonding interactions and several hydrophobic interactions of ligands with the active site of Leishmania major topoisomerase IB are responsible for their potent antileishmanial activity. These results can be exploited for structure-based computer-aided drug designing of new and selective leishmania topoisomerase inhibitors. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Interference with microtubule polymerization results in cell cycle arrest leading to cell death. Colchicine is a well-known microtubule polymerization inhibitor which does so by binding to a specific site on tubulin. A set of 3', 4'-bis (substituted phenyl)-4'H-spiro [indene-2, 5'-isoxazol]-1(3H)-one derivatives with known antiproliferative activities were evaluated for their tubulin binding modes. 3D structures of the derivatives were docked into the colchicine binding site of tubulin using GOLD 5.0 program under flexible ligand and semi-flexible receptor condition. The spiroisoxazoline derivatives bind tubulin in a similar manner to colchicine by establishing at least a hydrogen bonding to Cys241 as well as hydrophobic interactions with Leu255, Ile378 and Lys254 and few other residues at the binding pocket. It can be concluded that the spiroisoxazoline core structure common to the studied derivatives is a suitable scaffold for placing the antitubulin pharmacophoric groups in appropriate spatial positions required for tubulin binding activity. [ABSTRACT FROM AUTHOR]

• Novel indanone-carbamate (inspired from donepezil-rivastigmine) with anti-ChE activity were designed and synthesized. • X-ray structure analysis for the chiral center of 4a was assigned. • In vitro anti-ChE activities of the novel compounds were determined and AChE and BChE inhibition mechanisms of the most potent derivative were studied. • Interactions of derivative with predicted allosteric binding site (based on the result of the kinetic study) on AChE and BChE were studied using docking studies. • Good neuroprotective and anti-Aβ aggregation activities were shown for the potent compounds. New compounds containing indanone and carbamate moieties were designed based on the hybrid pharmacophore approach. The designed compounds were synthesized and fully characterized by using different methods such as IR, Mass, 1H NMR, 13C NMR, and HPTLC. In vitro inhibitory activities of all synthesized compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The compound 3-[(5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl) methyl] phenyl (4-methoxyphenyl) carbamate (4h) showed the best inhibitory activities with IC 50 values of 1.20 and 0.30 μM against AChE and BChE, respectively. In addition, this compound showed a β-amyloid self-aggregation inhibitory effect (86.8%), stronger than that of donepezil (45.5%). Moreover, significant neuroprotective activity on PC12 cells against H 2 O 2 induced cell death was demonstrated for compound 4h at 10 and 100 µM concentrations. Kinetic studies using the 4h confirmed a partial non-competitive mixed type of inhibition mechanism on both enzymes. Considering the suggested inhibition mechanism, molecular docking was used to predict the possible allosteric binding mode of 4h with both AChE and BChE enzymes. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multi-target anti-Alzheimer agents. Image, graphical abstract [ABSTRACT FROM AUTHOR]

[Display omitted] • New scaffolds for histamine H3 receptor ligands. • High drug-likeness of newly designed compounds by computational methods. • Selection of ligands by toxicological and ADME screening in silico. • Synthesis and proof of concept with one ligand selected. • Combination of diverse computational methods to the design of novel compounds with new scaffolds. During the past decades, histamine H 3 receptors have received widespread attention in pharmaceutical research due to their involvement in pathophysiology of several diseases such as neurodegenerative disorders. In this context, blocking of these receptors is of paramount importance in progression of such diseases. In the current investigation, novel histamine H 3 receptor ligands were designed by exploiting scaffold-hopping drug-design strategy. We inspected the designed molecules in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally molecular docking and dynamics simulation studies were performed to predict binding mode and binding free energy calculations, respectively. Among the designed structures, we selected compound d2 and its demethylated derivative as examples for synthesis and affinity measurement. In vitro binding assays of the synthesized molecules demonstrated that d2 has lower binding affinity (K i = 2.61 μM) in radioligand displacement assay to hH 3 R than that of demethylated form (K i = 12.53 μM). The newly designed compounds avoid of any toxicity predictors resulted from extended in silico and experimental studies, can offer another scaffold for histamine H 3 R antagonists for further structure–activity relationship studies. [ABSTRACT FROM AUTHOR]

• Virtual screening was used for identifying two novel ligands antagonizing PDGF-B. • Inhibitory activity of the ligands was evaluated using in vitro bioassay. • Binding free energies were calculated for the ligand-protein complexes. • The results of in silico calculations were in agreement with in vitro bioassay. • The results can be used for design of novel anti-PDGF-B drugs. Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. The purpose of the current study was to identify novel PDGF-B inhibitors using virtual screening methods. To this end, a combination of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug likeness filtering criteria, was applied to select anti-PDGF peptidomimetic candidates based on crystallography solved structure of an anti-PDGF-B monoclonal antibody named, MOR8457. In vitro biological assays of the selected compounds revealed two of them being active at micromolar IC 50 concentrations. The presented work can provide a framework for systematic peptidomimetic identification for anti-PDGF-B agents from large chemical libraries. [ABSTRACT FROM AUTHOR]