ABSTRACT
Macrodomain-I of the NSP3 (non-structural protein 3) is responsible for immune response hijacking in the SARS-CoV-2 infection known as COVID-19. In the omicron variant (B.1.1.529), this domain harbors a new mutation, V1069I, which may increase the binding of ADPr and consequently the infection severity. This macrodomain-I, due to its significant role in infection, is deemed to be an important drug target. Hence, using structural bioinformatics and molecular simulation approaches, we performed a virtual screening of the traditional Chinese medicines (TCM) database for potential anti-viral drugs. The screening of 57,000 compounds yielded the 10 best compounds with docking scores better than the control ADPr. Among the top ten, the best three hits-TCM42798, with a docking score of -13.70 kcal/mol, TCM47007 of -13.25 kcal/mol, and TCM30675 of -12.49 kcal/mol-were chosen as the best hits. Structural dynamic features were explored including stability, compactness, flexibility, and hydrogen bonding, further demonstrating the anti-viral potential of these hits. Using the MM/GBSA approach, the total binding free energy for each complex was reported to be -69.78 kcal/mol, -50.11 kcal/mol, and -47.64 kcal/mol, respectively, which consequently reflect the stronger binding and inhibitory potential of these compounds. These agents might suppress NSP3 directly, allowing the host immune system to recuperate. The current study lays the groundwork for the development of new drugs to combat SARS-CoV-2 and its variants.