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

Posted: 6 Feb 2020 Last revised: 10 Feb 2020

See all articles by Afsana Nahrin

Afsana Nahrin

University of Science and Technology Chittagong

Md. Junaid

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram

Syeda Samira Afrose

University of Chittagong

Muhammad Shaiful Alam

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram

Yeasmin Akter

Noakhali Science & Technology University

Tania Sharmin

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram

Nusrat Jahan Mouri

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram

S. M. Zahid Hosen

University of New South Wales

Date Written: January 15, 2020

Abstract

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.

Keywords: Colorectal Cancer, Cyclooxygenase-2, Density Functional Theory, XP Docking, Molecular Dynamics, ADME/T

Suggested Citation

Nahrin, Afsana and Junaid, Md. and Afrose, Syeda Samira and Alam, Muhammad Shaiful and Akter, Yeasmin and Sharmin, Tania and Mouri, Nusrat Jahan and Hosen, S. M. Zahid, Natural Hydroxycinnamic Acid Derivatives to Inhibit Cyclooxygenase-2 for Colorectal Cancer: Bridging Molecular Docking to Molecular Dynamics (January 15, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3530298

Afsana Nahrin (Contact Author)

University of Science and Technology Chittagong ( email )

Zakir Hossain Road, Foy’s Lake.
Chattogram, 4202
Bangladesh

Md. Junaid

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram ( email )

Baluchara, Chattogram Cantonment.
Chattogram, 4220
Bangladesh

Syeda Samira Afrose

University of Chittagong ( email )

Chittagong University Rd, Hathazari.
Chattogram, 4331
Bangladesh

Muhammad Shaiful Alam

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram ( email )

Baluchara, Chattogram Cantonment, Chattogram 4220
Chattogram, 4220
Bangladesh

Yeasmin Akter

Noakhali Science & Technology University ( email )

Sonapur, University Rd, 3814
Noakhali, 3814
Bangladesh

Tania Sharmin

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram ( email )

Baluchara, Chattogram Cantonment, Chattogram 4220
Chattogram, 4220
Bangladesh

Nusrat Jahan Mouri

Molecular Modeling Drug-design and Discovery Laboratory, BCSIR Laboratories, Chattogram ( email )

Baluchara, Chattogram Cantonment, Chattogram 4220
Chattogram, 4220
Bangladesh

S. M. Zahid Hosen

University of New South Wales ( email )

Liverpool, New South Wales 2170
Australia

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