Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

The 3CL-Protease appears to be a very promising medicinal target to develop anti-SARS-CoV-2 agents. The availability of resolved structures allows structure-based computational approaches to be carried out even though the lack of known inhibitors prevents a proper validation of the performed simulations. The innovative idea of the study is to exploit known inhibitors of SARS-CoV 3CL-Pro as a training set to perform and validate multiple virtual screening campaigns. Docking simulations using four different programs (Fred, Glide, LiGen, and PLANTS) were performed investigating the role of both multiple binding modes (by binding space) and multiple isomers/states (by developing the corresponding isomeric space). The computed docking scores were used to develop consensus models, which allow an in-depth comparison of the resulting performances. On average, the reached performances revealed the different sensitivity to isomeric differences and multiple binding modes between the four docking engines. In detail, Glide and LiGen are the tools that best benefit from isomeric and binding space, respectively, while Fred is the most insensitive program. The obtained results emphasize the fruitful role of combining various docking tools to optimize the predictive performances. Taken together, the performed simulations allowed the rational development of highly performing virtual screening workflows, which could be further optimized by considering different 3CL-Pro structures and, more importantly, by including true SARS-CoV-2 3CL-Pro inhibitors (as learning set) when available.     

Design,Synthesis, Molecular Docking,and Tumor Resistance Reversal Activity Evaluation of Matrine Derivative with Thiophene Structure

Nasopharyngeal carcinoma (NPC) frequently occurs in Southern China. The main treatments of NPC are chemotherapy and radiotherapy. However, chemo-resistance arises as a big obstacle in treating NPC. Therefore, there is a great need to develop new compounds that could reverse tumor drug resistance. In this study, eight matrine derivatives containing thiophene group were designed and synthesized. Structures of these 8 compounds were characterized by ¹H-NMR, ¹³C-NMR, and high-resolution mass spectrometer (HRMS). The cytotoxicity and preliminary synergistic effects of these 8 compounds were detected against nasopharyngeal carcinoma (NPC) cells and cisplatin-resistant NPC cells (CNE2/CDDP), respectively. Furthermore, the in vivo and in vitro tumor resistance reversal effects of compound 3f were evaluated. Moreover, docking studies were performed in Bclw (2Y6W). The results displayed that compound 3f showed synergistic inhibitory effects with cisplatin against CNE2/CDDP cells proliferation via apoptosis induction. Docking results revealed that compound 3f may exert its effects via inhibiting anti-apoptosis protein Bcl-w.     

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.     

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors,Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A_2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.     

基于虚拟现实的分子对接教学软件*

由于其强大的沉浸性和交互性等特征,虚拟现实技术在教育教学方面有着独特的优势。基于分子建模工具和虚拟现实技术构建了一种关于分子对接的教学软件,该软件将语音讲解、动画演示、分子可视化、交互操作等内容有机整合在虚拟现实环境中,从理论知识讲解和VR实验操作2个方面展开,深入浅出地讲解了分子对接的知识点,达到辅助教学的目的。     

Electrochemical Biosensor Design with Multi-walled Carbon Nanotube to Display DNA-Schiff Base Interaction

This paper demonstrates a Schiff base i. e. 5-(diethylamino)-2-((2,6-diethylphenylimino)methyl)phenol (5-DDMP) that was sensed by DNA biosensor. dsDNA was immobilized onto GCE modified with functionalized multi-walled carbon nanotubes to prepare a biosensor. The efficiency of dsDNA biosensor was determined and binding of 5-DDMP with dsDNA was searched by UV-vis spectrophotometry and differential pulse voltammetry. Molecular docking simulations between 5-DDMP and dsDNA were explored and as a result, a hydrogen bond and a π-π contact were observed between 5-DDMP and deoxyguanosine base (dG22) of the strand B, deoxyadenosine base (dA5) of the strand A, respectively. These studies could be useful for new anticancer drug design and development.     

Inhibitor Development against p7 Channel in Hepatitis C Virus

Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.     

Synthesis,anti‐inflammatory activity,and molecular docking study of novel azo bis antipyrine derivatives against cyclooxygenase‐2 enzyme

We have synthesized a new series of azo‐bis antipyrine derivatives from a one‐pot multicomponent Knoevenagel/Michael addition reaction of antipyrine, with a diversity of azo aldehydes in ethanol and L‐Proline as a catalyst under reflux condition. The anti‐inflammatory activity of the final products was assessed using the inhibition of albumin denaturation technique. Compound 3f showed an inhibitory effect with IC₅₀ values of 3.6 μM with respect to the standard anti‐inflammatory drug Aspirin, with IC₅₀ values of 2 μM. In addition, molecular docking was performed to confirm the in vitro results against the enzymatic inhibition activity of COX‐2 enzymes in which compound 3f showed good binding affinity with an inhibition constant (Ki) of 1.79 nM.     

Synthesis,spectral and quantum mechanical studies and molecular docking studies of Schiff base (E)2-hydroxy-5-(((4-(N-pyrimidin-2-yl)sulfamoyl)phenyl)imino)methyl benzoic acid from 5-formyl salicylic acid and sulfadiazine

A new Schiff base (E)2-hydroxy-5-(((4-(N-pyrimidin-2-yl)sulfamoyl)phenyl)imino)methyl benzoic acid (5FSADA) compound was synthesized by condensation of 5-formyl salicylic acid and sulfadiazine, and the product formed was characterized using FTIR and UV–Visible spectroscopy. The geometry was optimized using DFT. The FTIR were computed from DFT and is compared with experimental spectra, followed by detailed vibrational assignment, which shows that the experimental and simulated data is in close agreement. The UV–Vis spectrum calculated using TD-DFT, IEFPCM solvation model with DMSO as solvent. Wave function based properties like localized orbital locator, electron localization function and non-covalent interactions has been studied extensively. The physical properties (ADMET) of the compound 5FSADA indicated that the compound has excellent drug likeness and PASS studies showed that it has anti-infective properties, which is confirmed by a docking score of −9.0 ​kcal/mol.     

A molecular docking study of potential inhibitors and repurposed drugs against SARS-CoV-2 main protease enzyme

COVID-19 has affected millions of people. Although many drugs are in use to combat disease, there is not any sufficient treatment yet. Having critical role in propagation of the novel coronavirus (SARS-CoV-2) works Main Protease up into a significant drug target. We have performed a molecular docking study to define possible inhibitor candidates against SARS-CoV-2 Main Protease enzyme. Besides docking Remdesivir, Ribavirin, Chloroquine and 28 other antiviral inhibitors (totally 31 inhibitors) to Main Protease enzyme, we have also performed a molecular docking study of 2177 ligands, which are used against Main Protease for the first time by using molecular docking program Autodock4. All ligands were successfully docked into Main Protease enzyme binding site. Among all ligands, EY16 coded ligand which previously used as EBNA1-DNA binding blocker candidate showed the best score for Main Protease with a binding free energy of −10.83 ​kcal/mol which was also lower than re-docking score of N3 ligand (−10.72 ​kcal/mol) contained in crystal structure of Main Protease. After analyzing the docking modes and docking scores we have found that our ligands have better binding free energy values than the inhibitors in use of treatment. We believe that further studies such as molecular dynamics or Molecular Mechanic Poisson Boltzmann Surface Area studies can make contribution that is more exhaustive to the docking results.