Covalent simulations of covalent/irreversible enzyme inhibition in drug discovery: a reliable technical protocol

Abstract

Aim: Irreversible covalent inhibition of biological targets in disease pathogenesis is an emerging field in drug design. Computational techniques have assumed a critical role in understanding covalent enzyme inhibition. However, a gap currently exists with regards to the reliability and reproducibility of currently available protocols available in literature and open scientific forums. Methodology/results: Appropriate ligand and protein target are selected, docked covalently or noncovalently using respective docking tools. Both components are subjected to premolecular dynamic preparations. This was followed by parameterization of the ligand, protein and covalent complex, respectively. The production runs were initiated and the resulting trajectories are saved and analyzed. Conclusion: This protocol is reliable and reproducible, hence would advance the development of irreversible covalent inhibitors toward disease treatment.