Current Computer - Aided Drug Design - Volume 18, Issue 6, 2022

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a serious global healthcare crisis, so there is an emergence of identifying efficacious therapeutic options. In a setting where there is an unavailability of definitive medication along with the constant eruption of vaccine-related controversies, the drugrepositioning approach seems to be an ideal step for the management of COVID-19 patients. Fluoroquinolones (FQs) are commonly prescribed antibiotics for the treatment of genitourinary tract and upper respiratory tract infections, including severe community-acquired pneumonia. Research over the years has postulated multifaceted implications of FQs in various pathological conditions. Previously, it has been reported that few, but not all FQs, possess strong antiviral activity with an unknown mechanism of action. Herein, an interesting perspective is discussed on repositioning possibilities of FQs for the SARS-CoV-2 infections based on the recent in silico evidential support. Noteworthy, FQs possess immunomodulatory and bactericidal activity which could be valuable for patients dealing with COVID-19 related complications. Conclusively, the current perspective could pave the way to initiate pre-clinical testing of FQs against several strains of SARS-CoV-2.

Background: Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates. Objective: The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents. Methods: A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3·OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2. Results: The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using the MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better antimycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with an MIC value of 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties. Conclusion: These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.

Background: Network pharmacology based identification of phytochemicals in the form of cocktails against off-targets can play a significant role in the inhibition of SARS_CoV2 viral entry and its propagation. This study includes network pharmacology, virtual screening, docking and molecular dynamics to investigate the distinct antiviral mechanisms of effective phytochemicals against SARS_CoV2. Methods: SARS_CoV2 human-protein interaction network was explored from the BioGRID database and analysed using Cytoscape. Further analysis was performed to explore biological function, proteinphytochemical/ drugs network and up-down regulation of pathological host target proteins. This led to understand the antiviral mechanism of phytochemicals against SARS_CoV2. The network was explored through g: Profiler, EnrichR, CTD, SwissTarget, STITCH, DrugBank, BindingDB, STRING and SuperPred. Virtual screening of phytochemicals against potential antiviral targets such as M-Pro, NSP1, Receptor binding domain, RNA binding domain, and ACE2 discloses the effective interaction between them. Further, the binding energy calculations through simulation of the docked complex explain the efficiency and stability of the interactions. Results: The network analysis identified quercetin, genistein, luteolin, eugenol, berberine, isorhamnetin and cinnamaldehyde to be interacting with host proteins ACE2, DPP4, COMT, TUBGCP3, CENPF, BRD2 and HMOX1 which are involved in antiviral mechanisms such as viral entry, viral replication, host immune response, and antioxidant activity, thus indicating that herbal cocktails can effectively tackle the viral hijacking of the crucial biological functions of a human host. Further exploration through virtual screening, docking and molecular dynamics recognizes the effective interaction of phytochemicals such as punicalagin, scutellarin, and solamargine with their respective potential targets. Conclusion: This work illustrates a probable strategy for the identification of phytochemical-based cocktails and off-targets which are effective against SARS_CoV 2.

Background: The mechanisms that cause a patient's blood pressure to rise are diverse. Controlling blood pressure with monotherapy acting through a single pathway may be unachievable. Combining clinically used drug with herbal remedy can have two to five times greater antihypertensive response than monotherapy. Methods: This study examined the effects of aqueous extracts of large cardamom and ramipril on the redox biology of nitric oxide and vascular reactivity in the isolated aorta incubated with a nitro- L-arginine methyl ester. Molecular docking study was performed to predict the affinity of constituents of large cardamom extracts with the NOX 2 gene. Results: Nitric oxide (NO) levels, disordered antioxidant enzymes (glutathione and catalase), NADPH oxidase and lipid peroxidation were recovered when aqueous extract of large cardamomand ramipril were combined. A gradual increase in the percentage relaxation of acetylcholine in phenylephrine pre-contracted aorta indicates that the combination therapy prevents endothelial damage. Molecular docking study reveals the important phytoconstituents present in the large cardamom that can effectively bind with the NADPH oxidase for its antioxidant activity. Consculsion: According to our findings, it was evidenced that the large cardamom extract's vasoprotective action was was primarily due to its ability to restore endothelial redox biology by suppressing NADPH oxidase activity. Our findings suggest that ramipril's direct impact on the eNOS/NO system, along with the antioxidant properties of AELC, could have a synergetic benefit in the treatment of hypertension, as well as could minimize ramipril's existing side effects.

Aim: The aim of the study was to develop a method for use in computer-aided drug design. Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved. Objective: The objective was to conduct accurate prediction of enzyme-ligand binding mode conformation. Methods: A new computational protocol, MDO, is proposed for finding the structure of the ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of the enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures. Results: The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. Conclusion: The MDO protocol provides high-quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structurebased drug design.

Background: There is still little research on the anti-aging effect of Pogostemon cablin Benth (PCB) on human skin. In this paper, the mechanism of the anti-aging effect of PCB on human skin was studied by using network pharmacology and molecular docking methods. Objective: To analyze the pharmacological mechanism of PCB in the treatment of skin aging to provide a reference for new drug development and clinical application. Methods: Active ingredients and related targets of PCB and skin aging-related disease targets are obtained through public databases, and the "drug-disease-target" and protein-protein interaction (PPI) network diagrams were constructed with the help of software to screen the core targets; then GO analysis and KEGG pathway analyses were performed on the target; finally, the molecular docking between the components and the targets were verified. Results: 112 intersection targets of active compounds of skin aging and PCB were obtained after the screening. GO, and KEGG enrichment analysis found that these biological processes mainly focus on epithelial cell proliferation, aging, growth factors, longevity regulation pathway, cancer pathway, AGE-RAGE signal pathway, PI3K Akt signal pathway and IL-17 signal pathway. The molecular docking results showed quercetin, apigenin, irisnepalensis isoflavone, 3,23-dihydroxy- 12-oleorene-28-oleic acid, 5-hydroxy-7,4'- dimethoxyflavone and other major compounds were connected with TP53, JUN, HSP90AAL, AKT1 and MAPK1 through hydrogen bonds, and there was high binding energy between them. Conclusion: Through multi-target prediction and molecular docking verification, it shows that PCB has a strong effect in the treatment of skin aging, which provides a reference for further research.