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