In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening.

Farzin Hadizadeh,Amirhossein Sahebkar,Razieh Ghodsi,Salimeh Mirzaei,David Diller

doi:10.1155/2022/4004068

Abstract

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

Highlights

Microtubule-targeting agents (MTAs) are divided into two classes including microtubule stabilizers such as taxanes which bind to the paclitaxel binding site that stabilize the Computational and Mathematical Methods in Medicine tubulin polymer form and microtubule-destabilizing agents like vinca alkaloids and colchicine which bind to the colchicine and vinblastine binding site which inhibit tubulin polymerization into microtubules [6,7,8]
The findings revealed that ligand made one to two hydrogen bonds with protein (Figure 5)
Molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin

Summary

Introduction

Microtubules made of α- and β-tubulin heterodimers in eukaryotic cells and are vital components of the cytoskeleton which are involved in numerous cellular processes such as cell signaling, cell motility, and intracellular vesicle transport [1,2,3].Microtubules form highly dynamics mitotic spindles, which are vital for the suitable orientation and segregation of chromosomes; disruption of this equilibrium will lead to cell cycle arrest or cell apoptosis [4,5,6].Microtubule-targeting agents (MTAs) are divided into two classes including microtubule stabilizers such as taxanes which bind to the paclitaxel binding site that stabilize the Computational and Mathematical Methods in Medicine tubulin polymer form and microtubule-destabilizing agents like vinca alkaloids and colchicine which bind to the colchicine and vinblastine binding site which inhibit tubulin polymerization into microtubules [6,7,8]. Microtubules form highly dynamics mitotic spindles, which are vital for the suitable orientation and segregation of chromosomes; disruption of this equilibrium will lead to cell cycle arrest or cell apoptosis [4,5,6]. Despite the progress in the administration of microtubule targeting agents for the treatment of patients with cancer, currently, there are no FDA-approved tubulin inhibitors targeting the colchicine binding site [9]. This has encouraged medicinal chemists to design and discover the novel antimitotic agents that bind to the colchicine binding site for cancer therapy [10,11,12,13,14,15,16].

Methods

Results

Conclusion