Pharmacophore-based virtual screening and molecular docking simulation of terpenoid compounds as the inhibitor of sonic hedgehog protein for colorectal cancer therapy

Abstract

Colorectal cancer remains as the global health burden, which accounts for roughly 1 - 2 million new cases and 600,000 deaths per year. Hedgehog (Hh) signalling pathway has an imperative role in the mechanism and formation of colorectal cancer. Sonic hedgehog (Shh) protein is the most studied Hh protein because it is expressed by several tissues and experiments with Shh protein are generally applicable to other Hh homologs. In the present study, about 56,336 terpenoid compounds were screened through various computational methods using pharmacophore-based virtual screening and molecular docking simulation to determine their inhibitory potency against Shh protein. From molecular docking simulation results, about ten ligands have been selected according to their Gibbs free binding energies ΔGbinding) and the molecular interactions that formed during the formation of the terpenoid compound-Shh complex. Three terpenoid compounds, namely arganine J, asiaticoside A, and clinoposide A, shown a very high binding affinity toward Shh protein due to their lower ΔGbinding than robotnikinin, the standard ligand. Moreover, ADME-Tox, bioactivity, bioavailability, and pharmacology test results revealed that these compounds have better biological and pharmacological activity than the other terpenoid compounds. For further research, these terpenoid compounds can be used as a drug candidate for colorectal cancer therapy.