The coronavirus pandemic of 2019 (COVID-19) has adversely affected public health and the socioeconomic situation worldwide. Although there is no therapeutic drug to treat COVID, several treatment options are being considered to alleviate symptoms. Hence, researches on prophylactic treatment for COVID are being encouraged. Searching natural products is a rational strategy since it has served as a valuable source of lead compounds in drug discovery. In this study, three machine learning approaches, including Support Vector Machine (SVM), Random Forest (RF) and Gradient Boosting Machine (GBM), have been used to develop the classification model. The molecular docking was performed on AutoDock vina. Further, molecular dynamics (MD) simulation of the potential inhibitors was conducted using the AmberTools package. The accuracy for SVM, RF and GBM was found to be 60.45 %, 63.43 % and 64.93 %, respectively. Further, the model has demonstrated specificity range of 41.67 % to 50.00 % and sensitivity range of 74.32 % to 79.73 %. Application of the model on the NuBBE database, a repository of natural compounds, led us to identify 322 unique natural compounds, likely possessing anti-SARSCoV- 2activity. Further, molecular docking study has yielded three flavonoids and one lignoid compounds with comparable binding affinities to the standard compound. In addition, MD showed that these compounds form stable complexes with different magnitude of binding energy. The in silico investigations suggest that these four compounds likely demonstrate their anti-SARS-CoV-2activity by inhibiting the main protease enzyme. Our developed and validated in silico high-throughput investigations may assist in identifying and developing antiviral drug-like compounds from natural sources.
Dhaka Univ. J. Pharm. Sci. 21(1): 1-13, 2022 (June)
Hispolon (H) is a natural phenolic type of bioactive compound with diverse biological activities. The analgesic action of hispolon is due to the inhibition of prostaglandins biosynthesis. However, the molecular basis of this inhibition has not been explored. Therefore, we have performed theoretical investigations to evaluate the molecular basis of analgesic action of hispolon by docking with cyclooxygenase 2 (COX-2). Further, we have conducted high throughput in silico screening of a compound library consisting of 1699 compounds to get novel COX-2 inhibitors with better pharmacokinetic and analgesic properties. The docking study was conducted on AutoDock vina in PyRx 0.8 and the drug-like properties were calculated by MarvinSketch 15.6.29. Further, the pharmacokinetic properties were computed on online server PreADMET (https://preadmet.bmdrc.kr/). In the current investigations our virtual screening based on structure similarity search afforded 1699 compounds which were subjected for molecular docking with COX-2. These compounds were filtered based on binding affinity and binding poses which yielded 699 compounds. Further, sorting out based on drug-like properties produced a list of seven compounds (H1, H2, H3, H4, H5, H6 and H7). The in silico pharmacokinetic study revealed that these compounds possess good human intestinal absorption and moderate permeability through Caco-2 cell. Further, the Cbrain/Cblood ratio of these compounds indicate moderate penetrability of CNS except H3 and H5. The computational prediction of these compounds as substrates for P glycoprotein showed that H3 may act as both inhibitor and substrate for P glycoprotein. Moreover, molecular docking of H and its selected top hits revealed that all the ligands possess moderate to good binding affinity (-7.6 to -8.9 Kcal/mol) and associate with Val509 via hydrophobic interaction. Ligands H, H1, H2, H3, H4, and H7 can accommodate their aromatic ring inside the side pocket of COX-2 which is similar for accommodation of sulfonamide and methyl sulfone groups for celecoxib and rofecoxib, respectively. Therefore, it is expected that these ligands may exert their analgesic action by selectively blocking the biosynthesis of prostaglandins mediated by COX-2. Our computed properties may assist to develop hispolon derivatives with better pharmacokinetic and COX-2 inhibitory activity.
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