MOLECULAR DOCKING-GUIDED VIRTUAL SCREENING AND DE-NOVO DESIGN OF NOVEL COX-2 INHIBITORS FROM PHYTOCHEMICALS OF PHYSALIS MINIMA
TL;DR
The hybrid molecule VR6 represented a promising, pharmacokinetically sound lead candidate that warrants chemical synthesis and further in vitro biological evaluation as a safer anti-inflammatory therapeutics.
Abstract
Background: Selective cyclooxygenase-2 (COX - 2) inhibitors reduce gastrointestinal side effects but carry severe complications, promoting the search for safer alternatives from natural sources. Objectives: To identify protein COX - 2 inhibitor through molecular docking - guided virtual screening of phytoconstituents from Physalis minima and subsequent de-novo design of semisynthetic hybrids. Methods: A total of 93 Physalis minima phytoconstituents from the IMPPAT database were screened against the human COX-2 enzyme (5IKR.pdb). Using the top natural lead scaffold, an in silico library of 200 NSAID - caffeic/quinic acid hybrids was designed. Lead candidates were evaluated using MM-GBSA binding energy calculation. SWISS ADME profiling, and a 100 ns molecular dynamic simulation via the Desmond module. Results: Chlorogenic acid (IMPHY0011844) emerged as the top natural lead (binding affinity of -7.8 kcal/mol) from which a 200 in-house NSAID-caffeic acid and NSAID-quinic acid hybrids were designed. From the designed hybrids compound VR6 was evidenced strongest interactions with Arg120, Phe518, Gln192, and Ser530. ADME profiling predicted high gastrointestinal absorption, zero Lipinski violation, and lack of blood -brain barrier penetration. A 100ns molecular dynamics simulation verified that the VR6/5IKR complex exhibited highly stability, maintaining crucial interactions with Arg120 and Ser530 residues. Conclusion: The hybrid molecule VR6 represented a promising, pharmacokinetically sound lead candidate that warrants chemical synthesis and further in vitro biological evaluation as a safer anti-inflammatory therapeutics.