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Bromodomain-containing protein 9 (BRD9), a member of the bromodomain and extra terminal domain (BET) protein family, works as an epigenetic reader. BRD9 has been considered an essential drug target for cancer, inflammatory diseases, and metabolic disorders. Due to its high similarity among other isoforms, no effective treatment of BRD9-associated disorders is available. For the first time, we performed a detailed comparative analysis among BRD9, BRD7, and BRD4. The results indicate that residues His42, Gly43, Ala46, Ala54, Val105, and Leu109 can confer the BRD9 isoform selectivity. The predicted crucial residues were further studied. The pharmacophore model’s features were precisely mapped with some key residues including, Gly43, Phe44, Phe45, Asn100, and Tyr106, all of which play a crucial role in BRD9 inhibition. Docking-based virtual screening was utilized with the consideration of the conserved water network in the binding cavity to identify the potential inhibitors of BRD9. In this workflow, 714 compounds were shortlisted. To attain selectivity, 109 compounds were re-docked to BRD7 for negative selection. Finally, four compounds were selected for molecular dynamics studies. Our studies pave the way for the identification of new compounds and their role in causing noticeable, functional differences in isoforms and between orthologues.

Dithiocarbamate derivatives possess diverse biological activities. This work further expands their activity profile by identifying seven benzylamine-containing dithiocarbamate derivatives with piperazine and piperidine substitutions at the main moiety, and five piperazine-containing dithiocarbamates with various substitutions at the piperazine moiety as new inhibitors of α-glucosidase. Compounds bearing the benzylamine moiety exhibited more potent inhibition of the enzyme than the piperazine derivatives. Majority of the compounds non-competitively inhibited α-glucosidase that led to the identification of a new allosteric site on the enzyme with the help of molecular dynamics and docking studies. These studies suggest that the compounds regulate inhibition of the enzyme by binding to an allosteric site that is located in the vicinity of the active site. This is the first report on the allosteric inhibition of α-glucosidase by dithiocarbamate derivatives that provides insights into the mechanism of inhibition of the enzyme at molecular level. Moreover, it also explores new avenues for drug development of α-glucosidase inhibitors as antidiabetic drugs.

Synapsin I (SynI) is the most abundant brain phosphoprotein present at presynaptic terminals that regulates neurotransmitter release, clustering of synaptic vesicles (SVs) at active zones, and stimulates synaptogenesis and neurite outgrowth. Earlier studies have established that SynI displays pH-dependent tethering of SVs to actin filaments and exhibits a maximum binding around neutral pH, however, the effect of pH shift from acidic to basic on the conformational stability of SynI has not been explored yet. Another important aspect of SynIa is its O-GlcNAcylation (O-GlcNac) at the Thr87 position, which is responsible for the positive regulation of synaptic plasticity linked to learning and memory in mice. Furthermore, reduced levels of O-GlcNAc have been observed in Alzheimer's disease, suggesting a possible link to deficits in synaptic plasticity. In this study, the effect of pH and glycosylation on the structure and functional stability of SynIa is determined through molecular dynamics (MD) simulation approach. The 3D structure of SynIa was established via threading-based homology modeling methods. It was observed that the structure of SynIa adopts extended conformational changes as the pH shifts from acidic to basic, resulting in a compact conformation at pH 8.0. Moreover, the results obtained by comparing the glycosylated and unglycosylated protein indicated that the glycan moiety imparts stability to the protein by forming intramolecular hydrogen bond interactions with the protein residues. The results indicate that although O-GlcNAc moieties do not induce a significant change in SynIa structure they minimize protein dynamics, likely leading to enhanced protein stability.

Carbonic anhydrase-II (CA-II) catalyzes reversible hydration of carbon dioxide leading to the formation of bicarbonate and a proton. CA-II inhibitors act as biomarkers and therapeutic targets for various diseases such as epilepsy, glaucoma, leukemia, and cystic fibrosis. In the present work, a number of thiourea and benzylidene derivatives were evaluated as CA-II inhibitors. For this, detection of CA-II inhibition was tested through high throughput biochemical mechanism-based assay. Results indicated that thiourea derivatives exhibit remarkable inhibition activity with IC50 values ranging from 1.90 ± 1.30 to 25.90 ± 2.05 µM, when compared with the standard inhibitor acetazolamide IC50 = 0.13 ± 0.05. On the other hand, bezylidene derivatives showed weak inhibition potential with IC50 values in the range of 52.68 ± 0.47 to 348.57 ± 3.32 µM when compared with the thiourea derivatives; the Ez-Fit enzyme kinetics software was used for IC50 calculations from the percentage inhibition. In addition, 3T3 normal cell line was employed to determine the toxicity profile of identified inhibitors of CA-II. In silico modeling was performed to decipher the molecular nature of thiourea and benzylidene derivatives with key residues of carbonic anhydrase; results were in agreement with experiments related to inhibition of carbonic anhydrase.

Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CLpro) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CLpro) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.Communicated by Ramaswamy H. Sarma.

Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning method based on comprehensive integration of molecular signatures in liver cancer tissue and cell lines. First, we identify robust prognostic genes and two gene co-expression modules enriched in unfavorable prognostic genes based on two independent HCC cohorts, which showed great consistency in functional and network topology. Then, we screen 10 genes as potential target genes for HCC on the bias of network topology analysis in these two modules. Further, we perform a drug repositioning method by integrating the shRNA and drug perturbation of liver cancer cell lines and identifying potential drugs for every target gene. Finally, we evaluate the effects of the candidate drugs through an in vitro model and observe that two identified drugs inhibited the protein levels of their corresponding target genes and cell migration, also showing great binding affinity in protein docking analysis. Our study demonstrates the usefulness and efficiency of network-based drug repositioning approach to discover potential drugs for cancer treatment and precision medicine approach.

Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning method based on comprehensive integration of molecular signatures in liver cancer tissue and cell lines. First, we identify robust prognostic genes and two gene co-expression modules enriched in unfavorable prognostic genes based on two independent HCC cohorts, which showed great consistency in functional and network topology. Then, we screen 10 genes as potential target genes for HCC on the bias of network topology analysis in these two modules. Further, we perform a drug repositioning method by integrating the shRNA and drug perturbation of liver cancer cell lines and identifying potential drugs for every target gene. Finally, we evaluate the effects of the candidate drugs through an in vitro model and observe that two identified drugs inhibited the protein levels of their corresponding target genes and cell migration, also showing great binding affinity in protein docking analysis. Our study demonstrates the usefulness and efficiency of network-based drug repositioning approach to discover potential drugs for cancer treatment and precision medicine approach.

A series of spirooxindoles-based N-alkylated maleimide derivatives (AMIs) were synthesized and their inhibition profile also reported. Three component, one-pot [3 + 2] cycloaddition (32CA) reactions of isatin, amino acids and AMIs were found to proceed via syn-anti-azomethine ylides (AYs) to endo-addition of AMIs. These 32CA reactions present a very low activation enthalpy, 5.1 kcal·mol−1, as a consequence of the supernucleophilic character of AYs and the strong nucleophilic character of AMIs. The favorable electrostatic interactions taking place at the zwitterionic endo transition state structure are responsible for the endo stereoselectivity found in these polar 32CA reactions. The new hits of spirooxindoles-based AMIs were screened for their anticancer activity. Compounds 4e and 4f revealed the best anti-cancer activity against breast cancer cell line (MCF-7) that highly expressed human epidermal growth factor receptor (HER)-3 with the lowest IC50 < 6 µM. 4e and 4f were able to induce apoptosis by 47.26% and 55.36% with suppression of serine/threonine kinase (Akt). The latter is crucial mediator in the enhancement HER-3 which has essential function in HER-2-mediated tumor progression. Moreover, 4e and 4f were able to repress Akt-downstream genes (NF-kB and Bcl-2) expression and upregulating the expression of p21 in treated MCF-7 cells. Further, the newly synthesized spirooxindoles-based AMIs (4e and 4f) exhibited inhibitory potency for Akt and HER-2 that was supported by good binding affinity and docking interaction. Thus, 4e and 4f represent promising proapoptotic agents for breast cancer treatment.

Isomerism plays a key role in determining potency, selectivity and type of inhibition exhibited by enzyme inhibitors. We present 20 new benzylidene-hydrazinyl-thiazole inhibitors of α-glucosidase featuring positional isomerism of the methyl group at 3 and 4 positions of their piperidine ring. This structural property helped understand their potency and selectivity to the enzyme yielding new clues to α-glucosidase inhibition. The isomerism was pivotal to improving or deteriorating enzyme binding and potency of inhibition shown by the target compounds. Data from enzyme kinetics experiments were in agreement with docking and molecular dynamics simulations revealing a direct influence of isomerism on enzyme-inhibitor molecular interactions. Generally, the 4-methyl derivatives showed more selectivity toward the enzyme since they established more and stronger molecular contacts with the enzyme than their 3-methyl counterparts. However, the isomerism did not significantly affect the type of inhibition since majority of the compounds exhibited noncompetitive enzyme inhibition except for one. Our work provides essential and interesting clues to understanding α-glucosidase inhibition by thiazole isomers that would help explore new avenues to designing and developing better α-glucosidase inhibitors as antidiabetic drugs.

Interleukin-4 (IL-4), an anti-inflammatory cytokine plays significant in the development of various diseases especially asthmatic allergies. Previous structural and functional studies of IL-4 with its receptor bring forth different types of inhibitors to block their interaction but each of them failed in clinical trials. Since, no synthetic molecules have been identified against IL-4, so far. Therefore, 21 in-house tested IL-4 inhibitors were blindly docked over the entire surface of IL-4 to predict a suitable and druggable binding site as the crystal structure of IL-4 protein in complex with ligand has not been reported yet. After binding site prediction, both ligand-based and structure-based pharmacophore were generated to screen three ZINC libraries (24.5 M) i.e. purchasable, natural product and natural derivative. A total 5,800 top-scored compounds were further subjected towards score-based screening to find the potential leads. Following protein-ligand interaction fingerprints (PLIF) and molecular visualization of selected hits, six top-scored compounds (five from purchasable and one from natural product library) were further moved towards their stability dynamics, followed by their absolute binding free energy and residue-based energy decomposition calculation by MM-GBSA method. These efforts help us to reveal the key factors responsible for ligand binding that might help to improve the binding and stability of these newly discovered hits by structural modifications. Communicated by Freddie R. Salsbury

The Galaninergic system consist of Galanin and its receptors, involved in neuromodulation and neurotransmission. Galanin regulate its physiologic and pathologic functions by interacting with three G-protein coupled receptors; GalR1, GalR2 and GalR3. The widespread distribution of Galanin and its receptor subtypes in central and peripheral nervous system makes them an attractive drug target for the treatment of neurological diseases. However, subtypes selective ligands paucity and little structural information related to either Galanin receptors and Galanin receptor-ligand complexes hampered the structure-based drug design. Thus computational modeling characterization strategy was utilized for Galanin receptor 3D structure prediction and subtypes ligands binding selectivity. Reported ligands with experimental activity were docked against the homology model of Galanin receptors. Further, the MD simulation and binding free energy calculation were carried out to determine the binding interactions pattern consistency and selectivity towards receptor subtype. Results of binding free energy of per residue indicate key contribution of GalR1 Phe115 and His267 in the selective binding of ligands while Tyr103, Tyr270 and His277 play major role in the selective binding of GalR3 ligands. Our study provide rationale for further in silico virtual screening of small molecules for the development of selective ligands against Galanin receptor subtypes. Communicated by Ramaswamy H. Sarma

Highlights • Multistep SBVS of CAS antiviral database is performed for the identification of potent and effective inhibitors against 3CLPro of SARS-CoV-2. • Molecular docking and MD simulation studies demonstrated that the hit compounds stabilized inside the binding pocket of the target protein and exhibit complementarity with the active site residues. • The identified hits can be further used for in vitro and in vivo studies against SARS-CoV-2., The pandemic of COVID-19 has an unprecedented impact on global health and economy. The novel SARS-CoV-2 is recognized as the etiological agent of current outbreak. Because of its contagious human-to-human transmission, it is an utmost global health emergency at present. To mitigate this threat many scientists and researchers are racing to develop antiviral therapy against the virus. Unfortunately, to date no vaccine or antiviral therapeutic is approved thus there is an urgent need to discover antiviral agent to help the individual who are at high risk. Virus main protease or chymotrypsin-like protease plays a pivotal role in virus replication and transcription; thus, it is considered as an attractive drug target to combat the COVID-19. In this study, multistep structure based virtual screening of CAS antiviral database is performed for the identification of potent and effective small molecule inhibitors against chymotrypsin-like protease of SARS-CoV-2. Consensus scoring strategy combine with flexible docking is used to extract potential hits. As a result of extensive virtual screening, 4 hits were shortlisted for MD simulation to study their stability and dynamic behavior. Insight binding modes demonstrated that the selected hits stabilized inside the binding pocket of the target protein and exhibit complementarity with the active site residues. Our study provides compounds for further in vitro and in vivo studies against SARS-CoV-2., Graphical Abstract Image, graphical abstract

Inhibitor of kappa B kinase subunit β (IKKβ) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds., Pharmaceutical chemistry, Theoretical chemistry, Inhibitors of IKKβ, Thienopyridine analogues, Quantum mechanics, 3D-QSAR Studies, Chemical reactivity descriptors.

Tumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC50 32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.

Background: The tradition of khat chewing has been deep-rooted in the African and Arabian Peninsula for centuries. Due to its amphetamine-like psycho-stimulant or euphoric effect, khat has been used by millions in Somalia, Ethiopia, Saudi Arabia and Yemen. The long-term use of khat can induce many major health outcomes, which may be serious and irreversible. Objective: Prolonged use of khat constituents has been associated with different types of cancers such as prostatic, breast and ovarian cancer. However, it has been very difficult to identify the molecular targets involved in khat carcinogenesis that interact with the Khat constituents by in vitro/in vivo experimental tools. Methods: In silico tools were used to predict potential targets involved in the carcinogenesis of khat. Pass on-line prediction server was used for the prediction of a potential molecular target for khat constituents. Molecular Dynamics simulation and MM-GBSA calculation of the predicted target were carried out. Results: Molecular Dynamics simulation and MM-GBSA calculation revealed that among khat constituents, β-sitosterol showed a high binding affinity towards 17β-HSD5. On the other hand, this study highlights for the first time some new interactions, which were observed in the case of cathine, cathinone and nerol during the simulation. Conclusion: In silico molecular dynamic simulation tools were used for the first time to investigate the molecular mechanism of widely used leaves of psychoactive khat (Catha edulis) constituent. The present study provides deep insight to understand the effect of khat constituents involved in the impairment of the reproductive system and its binding to 17β-HSD5. ADMET profiling also suggested that few khat constituents do not fulfill the requirements of the Lipinski rule of five i.e. poor absorption and blood-brain barrier impermeability.

Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CL

In the present study, we have estimated the binding affinities of nine flavonoids with cAMP sensing protein kinase A (PKA) by molecular docking. Furthermore, their potential roles in stimulating insulin secretion in a PKA-dependent manner were evaluated in isolated islets using H-89, a PKA inhibitor. Among selected flavonoids, i.e. eriodictyol, kaempferol, hesperetin, naringin, apigenin, hesperidin, quercetin, naringenin and rutin, we found that eriodictyol, kaempferol, and naringenin speculated the best binding interactions with crucial residues in PKA binding pocket. Glucose-dependent insulin secretion was inhibited by eriodictyol, kaempferol and naringenin of 92%, 87%, and 89%, respectively in isolated islets co-incubated with H-89. In contrast, quercetin also got binding with PKA; however, showed no significant PKA-dependent insulinotropic activity in vitro. Rutin showed the least docking interactions with PKA, reflects well in vitro by exhibiting a PKA-independent mode of action. Naringin, hesperetin, hesperidin, and apigenin showed favourable docking affinities with PKA but not with the hot spot residues. Although naringin and hesperetin mimic well in vitro by showing PKA-independent mode of action, hesperidin and apigenin were still exhibited the PKA-dependent effect. The present work suggests that few of the selected flavonoids have strong potential to be used as alternative insulin secretagogues in diabetic treatment.

Casein kinase-II, a member of protein kinase family, plays significant role in different cellular processes such as cell growth, differentiation, proliferation, gene expression, and embryogenesis. Being a potent suppressor of apoptosis, it serves as a significant link for its association with various types of malignancies such as colorectal and breast cancer. To overcome its pathological role in various cancerous diseases, CK-II procures great consideration as a therapeutic target. This study aimed at understanding the binding mechanism and structural properties of benzimidazole derivatives by utilizing various computational tools including docking simulation, three-dimensional quantitative structure activity relationships and molecular dynamic simulation. Structure-based 3D-QSAR techniques such as CoMFA and CoMSIA models, were established from the conformations gained by protein-ligand docking approach. The attained models have showed a good extrapolative power for internal as well as external validation. Moreover, MD simulation was carried out to explain the detailed binding mechanism and the comparison of inhibitor's binding mode with diverse biological activities. A good correlation was observed among docking studies, MD results, and contour map analysis. Interestingly new molecules were designed using detail structural information from MD simulation, showed higher potency of inhibition (pIC

Eriodictyol, a flavonoid isolated from Lyonia ovalifolia, was found to be the most potent insulin secretagogue in our preliminary studies. Here, we explored mechanism(s) of insulin secretory activity of eriodictyol in vitro and in vivo. Mice islets and MIN6 cells were incubated in basal and stimulatory glucose containing eriodictyol with or without agonist/antagonist. Secreted insulin and cAMP contents were measured using ELISA kits. K+- and Ca2+-channels currents were recorded with patch-clamp technique. Oral glucose tolerance test and plasma insulin was evaluated in non-diabetic and diabetic rats. Eriodictyol stimulated insulin secretion from mice islets and MIN6 cells only at stimulatory glucose concentrations with maximum effect at 200μM. Eriodictyol showed no pronounced effect on inward rectifying K+ and Ca2+ currents. Furthermore, in KCl depolarized islets, in the presence of diazoxide, insulin secretory ability of eriodictyol was enhanced. IBMX, a phosphodiesterase inhibitor, significantly (P

Tambulin, a flavonol isolated from Zanthoxylum armatum, showed potent insulin secretory activity in our preliminary anti-diabetic screening. Here, we explored the insulin secretory mechanism(s) of tambulin focusing in glucose-dependent, KATP ‒ and Ca2+‒channels dependent, and cAMP-PKA pathways. Mice islets and MIN6 cells were incubated with tambulin in the presence of pharmacological agonists/antagonists and the secreted insulin was measured using mouse insulin ELISA kit. The intracellular cAMP was measured by an acetylation cAMP ELISA kit. Tambulin (200 μM) showed potent insulin secretory activity only at stimulatory glucose (11–25 mM) concentrations; however, no change in insulin release was observed at basal glucose both in mice islets and MIN6 cells. Notably, in the presence of diazoxide, a KATP channel opener; the incomplete inhibition of tambulin-induced insulin secretion was observed whereas, complete inhibition was found using verapamil, an L-type Ca2+ channel blocker. Furthermore, the insulinotropic potential of tambulin was amplified in tolbutamide treated, and depolarized islets suggest tambulin’s target other than tolbutamide. Tambulin showed no additive effect in the IBMX-induced intracellular cAMP; whereas, exerted an additive effect in the IBMX-induced insulin secretion. Furthermore, tambulin-induced insulin secretion was dramatically inhibited by PKA inhibitor (H-89), while moderate inhibition was found by using PKC inhibitor (calphostin C). Molecular docking studies also showed the best binding affinities of tambulin with PKA suggest the PKA dependent signaling cascade is involved more in tambulin-induced insulin secretion. Based on these findings, it is concluded that tambulin stimulates insulin secretion in a Ca2+ channel-dependent but KATP channel-independent manner, most likely by activating the cAMP-PKA pathway.

Tambulin, a flavonol isolated from Zanthoxylum armatum, showed potent insulin secretory activity in our preliminary anti-diabetic screening. Here, we explored the insulin secretory mechanism(s) of tambulin focusing in glucose-dependent, K

N-Myristoyltransferase (NMT) is a cytosolic monomeric enzyme involved in the allocation of the myristoyl group to the aminoterminal of glycine in several viral and eukaryotic cellular proteins. NMT has been validated as a potential drug target against kinetoplastid for parasitic protozoa. A multistep virtual screening protocol based on the pharmacophore modeling, molecular docking, and molecular dynamics simulation was carried out. Initially, Maybridge database was virtually screened via a validated pharmacophore model. The effective pharmacophore models were accompanied with exclusion volumes to improve their receiver operating characteristic curve to identify potential NMT inhibitors. The hits identified as actives based on the 3D-pharmacophore model were evaluated by molecular docking studies. In stepwise screening, six compounds were shortlisted for the dynamic simulation to get insights into their binding mode. In conclusion, this study provides fundamental information about the architecture of the binding site and some crucial residues that may provide insights into the development of new antiparasitic agents.

cAMP-dependent guanine nucleotide exchange factor (Epac) is a key regulator in signal transduction and represents an excellent drug target to be investigated against various diseases. To date, very few modulators selective for Epac are available; however, there is still an unmet need of isoform-selective inhibitors. In the present study, ligand-based pharmacophores were designed to investigating structurally diverse molecules as Epac2 inhibitors. Pharmacophore models were developed using reported allosteric site inhibitors. The developed models were used to screen 95 thousand compounds from the National Cancer Institute (NCI), Maybride, and our in-house ICCBS Database. The binding mode and efficiency of the screened hits was investigated using molecular docking simulation on the allosteric site of Epac2 apo-protein (PDB ID: 2BYV) followed by ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling Furthermore, obtained in silico screened hits were subjected to in vitro assay for insulin secretion. We identified, three lead molecules RDR02145, AAK-399, and AAD-026 reducing, insulin secretion. Remarkably, a higher inhibitory effect on insulin secretion was observed in AAK-399, and AAD-026 as compared to that of standard Epac2 non-competitive allosteric site inhibitor, MAY0132. Furthermore, Dynamic simulation studies of lead compounds proved the structural stability of the Epac2 auto-inhibited state. These findings underline the potential of these compounds as valuable pharmacological tools for designing future selective probes to inhibit the Epac-mediated signaling pathway.

5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones 1-43 were synthesized in a "one-pot" three component reaction and structurally characterized by various spectroscopic techniques such as 1H, 13C NMR, EI-MS, HREI-MS, and IR. All compounds were evaluated for their in vitro urease inhibitory activity. It is worth mentioning that except derivatives 1, 11, 12, and 14, all were found to be more potent than the standard thiourea (IC50 = 21.25 ± 0.15 µM) and showed their urease inhibitory potential in the range of IC50 = 3.70 ± 0.5-20.14 ± 0.1 µM. Structure-activity relationship (SAR) was rationalized by looking at the varying structural features of the molecules. However, molecular modeling study was performed to confirm the binding interactions of the molecules (ligand) with the active site of enzyme.

Urease enzyme (EC 3.5.1.5) has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship) advance studies were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q2) value of 0.597 and correlation coefficients (r2) of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q2 and r2 of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r2pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.

In the current study, quantitative three-dimensional structure-activity-relationship (3D-QSAR) method was performed to design a model for new chemical entities by utilizing pyrazolopyrimidines. Their inhibiting activity on receptor IL-2 Itk correlates descriptors based on topology and hydrophobicity. The best model developed by ligand-based (atom-based) approach has correlation-coefficient of r2: 0.987 and cross-validated squared correlation-coefficient of q2: 0.541 with an external prediction capability of r2: 0.944. Whereas the best selected model developed by structured-based (receptor-based) approach has correlation-coefficient of r2: 0.987, cross-validated squared correlation-coefficient of q2: 0.637 with an external predictive ability of r2: 0.941. The statistical parameters prove that structure-based gave a better model to design new chemical scaffolds. The results achieved indicated that hydrophobicity at R1 location play a vital role in the inhibitory activity and introduction of appropriately bulky and strongly hydrophobic-groups at position 3 of the terminal phenyl-group which is highly significant to enhance the activity. Six new pyrazolopyrimidine derivatives were designed. Docking simulation study was carried out and their inhibitory activity was predicted by the best structure based model with predictive activity of ranging from 8.43 to 8.85 log unit. The interacting residues PHE435, ASP500, LYS391, GLU436, MET438, CYS442, ILE369, VAL377 of PDB 4HCT were studied with respect to type of bonding with the new compounds. This study was aimed to search out more potent inhibitors of IL-2 Itk.

Background Discovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme. Results Thirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a–z and 5a–s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC50 = 17.6 ± 0.23 µM) and 5l (IC50 = 17.2 ± 0.44 µM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC50 = 21.2 ± 1.3 µM). Whereas, compounds 4a–b, 4d–e, 4g–h, 4j–4r, 4x, 4z, 5b, 5e, 5k, 5n–5q having IC50 values in the range of 22.7 ± 0.20 µM–43.8 ± 0.33 µM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural–activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity. Conclusions This research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.Graphical abstract:STD. Thiourea (IC50 = 21.2 ± 1.3 µM) Electronic supplementary material The online version of this article (doi:10.1186/s13065-015-0140-1) contains supplementary material, which is available to authorized users.