Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation

The new coronavirus SARS-COV-2, which emerged in late 2019 from Wuhan city of China was regarded as causing agent of the COVID-19 pandemic. The primary protease which is also known by various synonymous i.e., main protease, 3-Chymotrypsin-like protease (3CL(PRO)) has a vital role in the replication of the virus, which can be used as a potential drug target. The current study aimed to identify novel phytochemical therapeutics for 3CL(PRO) by machine learning-based virtual screening. A total of 4,000 phytochemicals were collected from deep literature surveys and various other sources. The 2D structures of these phytochemicals were retrieved from the PubChem database, and with the use of a molecular operating environment, 2D descriptors were calculated. Machine learning-based virtual screening was performed to predict the active phytochemicals against the SARS-CoV-2 3CL(PRO). Random forest achieved 98% accuracy on the train and test set among the different machine learning algorithms. Random forest model was used to screen 4,000 phytochemicals which leads to the identification of 26 inhibitors against the 3CL(PRO). These hits were then docked into the active site of 3CL(PRO). Based on docking scores and protein-ligand interactions, MD simulations have been performed using 100 ns for the top 5 novel inhibitors, ivermectin, and the APO state of 3CL(PRO). The post-dynamic analysis i.e,. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis reveal that our newly identified phytochemicals form significant interactions in the binding pocket of 3CL(PRO) and form stable complexes, indicating that these phytochemicals could be used as potential antagonists for SARS-COV-2.