Phytoconstituents from Markhamia tomentosa bind to HPV oncoprotein with apoptogenic potential: A Molecular Modeling Approach.

Abstract

Rational drug design refers to the development of drug molecules based on the knowledge of the structures and functions of biological targets. Interaction of Markhamia tomentosa phytoconstituents with molecular drug targets to exert its anticancer property is evaluated via in-silico study. Identified phytoconstituents from M. tomentosa were retrieved from PubChem database and docked in predicted active sites of HPV 16 E6, caspase -3 and caspase -8 targets using AutoDock Vina from PyRx software. Screening for drug-likeness; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions was carried out with the use of SwissADME and pkCSM web servers. Standard melphalan and co-crystallized ligands of caspases -3 and -8 enzymes were used to validate protein-ligand interactions. Molecular dynamic simulation was used to validate the stability of the hit molecules complexed with caspases -3 and -8. All eleven tested phytoconstituents from M. tomentosa showed binding affinity for HPV with docking scores range of - 5.4 to -2.6 kcal/mol. Ajugol, carnosol, luteolin and phytol showed good docking energy range of -6.8 to -3.6 kcal/mol; and -4.8 to -1.9 kcal/mol for the active sites of caspases -3 and -8 targets respectively. Based on docking scores, drug-likeliness, and ADMET predictions, luteolin and carnosol were selected as hit compounds. These molecules were found to be stable within the binding site of caspase -3 target throughout the 40ns simulation time. These findings identified hit ligands from M. tomentosa phyto-constituents that inhibit expression of HPV 16 E6 oncogene with stimulation of caspases -3 and -8 targets