In silico approach to design new cyclooxygenase-2 (COX-2) inhibitors based on MM/QM and ADMET analysis

Abstract

In spite of the availability of inhibitors targeting the Cyclooxygenase-2 (COX-2) enzyme, there persists a need for current medications, not solely within the realm of non-steroidal anti-inflammatory drugs (NSAIDs) but also in diverse therapeutic domains such as cancer prevention and Alzheimer's disease treatment. Amidst the COVID-19 pandemic in 2019, COX-2 selective inhibitors emerged as highly sought-after NSAIDs due to their efficacy in pain alleviation and prevention of inflammatory conditions. With an in-silico approach {amalgamation of Quantum Mechanics (QM) and Molecular Mechanics (MM)}. we evaluated a series of 70 new and potential anti-inflammatory compounds based upon the derivatives of arylhydrazone, pyrrolo [3,4-d] pyridazinone, 1,5-diphenyl pyrazole, and 2-imidazoline that interact with the COX-2 receptor (PDB ID: 1CX2) via molecular docking. 14 top-ranked compounds comparable to a standard drug (SC-58) were selected for drug-likeness properties such as physicochemical and ADMET. Subsequently, a selection of 12 highly promising molecules was made, and the target prediction tool effectively identified protein targets for the COX-2 compound. Following this, FMO (Frontier Molecular Orbital) and MEP (Molecular Electrostatic Potential) studies were conducted, revealing increased stability in the drug complexes due to a larger HOMO-LUMO gap. Additionally, a noteworthy electrophilicity index indicated favorable electrophilic behavior. The study also highlighted new advantageous binding sites for these 12 analogues, suggesting their importance as potential candidates for non-steroidal anti-inflammatory drugs in the treatment of inflammatory diseases.