Identification of potent inhibitors of HDAC2 from herbal products for the treatment of colon cancer: Molecular docking, molecular dynamics simulation, MM/GBSA calculations, DFT studies, and pharmacokinetic analysis

by Madan Khanal, Arjun Acharya, Rajesh Maharjan, Kalpana Gyawali, Rameshwar Adhikari, Deependra Das Mulmi, Tika Ram Lamichhane, Hari Prasad Lamichhane

The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, R_g, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.