Hybrid Approach to Identifying Druglikeness Leading Compounds against COVID-19 3CL Protease.

ABSTRACT

SARS-CoV-2 is a positive single-strand RNA-based macromolecule that has caused the death of more than 6.3 million people since June 2022. Moreover, by disturbing global supply chains through lockdowns, the virus has indirectly caused devastating damage to the global economy. It is vital to design and develop drugs for this virus and its various variants. In this paper, we developed an in silico study-based hybrid framework to repurpose existing therapeutic agents in finding drug-like bioactive molecules that would cure COVID-19. In the first step, a total of 133 drug-likeness bioactive molecules are retrieved from the ChEMBL database against SARS coronavirus 3CL Protease. Based on the standard IC50, the dataset is divided into three classes active, inactive, and intermediate. Our comparative analysis demonstrated that the proposed Extra Tree Regressor (ETR)-based QSAR model has improved prediction results related to the bioactivity of chemical compounds as compared to Gradient Boosting-, XGBoost-, Support Vector-, Decision Tree-, and Random Forest-based regressor models. ADMET analysis is carried out to identify thirteen bioactive molecules with the ChEMBL IDs 187460, 190743, 222234, 222628, 222735, 222769, 222840, 222893, 225515, 358279, 363535, 365134, and 426898. These molecules are highly suitable drug candidates for SARS-CoV-2 3CL Protease. In the next step, the efficacy of the bioactive molecules is computed in terms of binding affinity using molecular docking, and then six bioactive molecules are shortlisted, with the ChEMBL IDs 187460, 222769, 225515, 358279, 363535, and 365134. These molecules can be suitable drug candidates for SARS-CoV-2. It is anticipated that the pharmacologist and/or drug manufacturer would further investigate these six molecules to find suitable drug candidates for SARS-CoV-2. They can adopt these promising compounds for their downstream drug development stages.