Synthesis, Pharmacokinetic, Molecular Docking, and Molecular Dynamics Simulation of 2-Styrylchromone Derivatives as Potential Inhibitor of Human Kinesin Eg5

Alfinda Novi Kristanti1,2,Email

Nanik Siti Aminaha2

Imam Siswanto1,3

Andika Pramudya Wardana4

Muhammad Ikhlas Abdjan5

Ana Rizki Khoirunisak1

Evi Noviana1

1Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Komplek Kampus C UNAIR, Jl. Mulyorejo, Surabaya 60115, Indonesia.
2Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga, Jawa Timur 60132, Indonesia.
3Bioinformatic Laboratory, UCoE Research Center for Bio-Molecule Engineering, Universitas Airlangga, Surabaya 60115, Indonesia.
4Department of Chemistry, Faculty of Mathematics and Natural Sciences, State University of Surabaya, Lakarsantri 60213 Indonesia.
5Department of Mathematics and Natural Sciences, Faculty of Science and Technology, Universitas Airlangga, Komplek Kampus C UNAIR, Jl. Mulyorejo 60115, Surabaya, Indonesia.

Abstract

Synthesis and characterization of 2-styrylchromone derivatives had been done through aldol condensation between 2-methylchromone and various cinnamaldehyde with modified substituent groups on the benzene ring, such as –Br and –OCH3. Pharmacokinetic studies provide some information on the drug-likeness, bioavailability, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of these 2-styrylchromone derivatives. Meanwhile, a structure-based approach was performed to study the potential of 2-styrylchromones as an inhibitor of the kinesin Eg5. The activity of kinesin Eg5 was found in the regulation of the mitosis phase on cancer cells, so it has a promising target potential in cancer therapy. The results show that MT2 and MT3 have promising potential as Eg5 kinesin inhibitors from a thermodynamic aspect. The prediction of binding free energy (∆Gbind) using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach shows the ∆Gbind (kcal mol-1) of MT3-Eg5: -33.89 ± 0.28 and MT4-Eg5: -21.88 ± 0.22. Besides, Energy decomposition (∆Gresiduebind) presented 12 key binding residues which were identified as responsible for the interaction with inhibitors, such as E100, R103, S104, P105, W111, I120, P121, Y195, L198, E199, A202, and A203. The obtained results demonstrated how 2-styrylchromone derivatives could be considered against the kinesin Eg5 at the molecular level.

Synthesis, Pharmacokinetic, Molecular Docking, and Molecular Dynamics Simulation of 2-Styrylchromone Derivatives as Potential Inhibitor of Human Kinesin Eg5