Natural Hydroxycinnamic Acid Derivatives to Inhibit Cyclooxygenase-2 for Colorectal Cancer: Bridging Molecular Docking to Molecular Dynamics

Colorectal cancer (CRC) is one of the most incidental and deadliest cancer worldwide, accounting for a million new cases every year. Various scientific studies have demonstrated that inhibition of cyclooxygenase-2 (COX-2) signaling by COX-2 inhibitors is an effective strategy for controlling colorectal carcinogenesis. COX-2 belongs to the family of myeloperoxidases and is over-expressed in CRC cells. The pro-tumorigenic effects are contributed to the inhibition of apoptosis, increased cell proliferation, induction of angiogenesis, and stimulation of inflammation, immunosuppression, and conversion of carcinogens. It regulates the rate-limiting biosynthesis of prostaglandins (PGs) which has been thought to positively regulate the CRC process. An abundance of one of its principle metabolic products, prostaglandin E2 (PGE2) is known to trigger the activation of β-catenin signaling, or canonical Wnt pathway through a number of steps, thus mediating cell proliferation. It is also known to transactivate EGFR, an important step for apoptosis. All these steps make COX-2 an attractive and effective target for managing CRC. In our study, we focused on six naturally occurring hydroxycinnamic acid derivatives named Cinnamic acid, p-Coumaric acid, Ferulic acid, Caffeic acid, Chlorogenic acid, and Rosmarinic acid on the various scientific reporting of their anti-cancer activity. Firstly, we optimized the derivatives on Gaussian 09 by employing density functional theory (DFT) using the B3LYP/6-31G (d, p) basis set. The dipole moment, electronic energy, enthalpy, and Gibbs free energy was calculated, and the hardness and softness of the molecules determined from frontier molecular orbitals (HOMO and LUMO). After optimization, we conduct a glide XP docking against the active site of COX-2, in order to study the conformation, orientation and molecular interactions of the complexes so formed. A molecular dynamic (MD) simulation study was later performed on the best candidates to further validate the docking outcomes. Both docking and dynamic simulation result has revealed that two derivatives, Rosmarinic acid, and Caffeic acid displayed strong interaction with important residues Arg120, Tyr385, and Ser530, necessary for the inhibitory action of COX-2. An ADME/T and Drug-likeness study has also predicted good pharmacokinetic profile, lower toxicity and safe oral use for both the compounds. All these results point towards the possibility of the derivatives to potentially restrict COX-2 activity, preclude the biosynthesis of PGs in CRC and halt the uncontrolled proliferation of cancer cells.