De novo design of novel spike glycoprotein inhibitors using e-pharmacophore modeling, molecular hybridization, ADMET, quantum mechanics and molecular dynamics studies for COVID-19

ABSTRACT

The pandemic COVID-19, caused by SARS-COV-2, has been a global concern and burden since April 2020 due to high contagiousness and pathogenesis. A great effort is being devoted to identify and investigate different druggable targets for SARS-COV-2 drug discovery. At least three targets have been identified among them is the spike glycoprotein which facilitates viral entry by binding to angiotensin converting enzyme (ACE-2 receptor) in host cell. In the current study, different computational tools were used to design potential cell entry inhibitors targeting spike glycoprotein. The essential pharmacophoric features were identified by e-pharmacophore mapping and fragments virtual screening was run using three different libraries. Docking scores were used to select the best fragments which were linked to afford novel molecules. The designed molecules were filtered via molecular docking, MM-GBSA free energy calculation, ADMET, drug-like properties and DFT calculations. Moreover, synthetic feasibility of the best ligands was studied. These ligands would be envisioned as potential leads for SARS-COV-2 cell entry inhibition and could be explored further towards COVID-19 drug discovery and development.