Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations.

Muhammad Khattab,Ahmed A Al‐Karmalawy

doi:10.3389/fchem.2021.628398

Muhammad Khattab, Ahmed A Al‐Karmalawy

Open Access

https://doi.org/10.3389/fchem.2021.628398

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Abstract

Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.

Highlights

Microtubules play a key role in the invasion and metastatic spread of tumor cells, depending on its crucial roles in mitosis, signaling, trafficking, proliferation, and migration of eukaryotic cells (Honore, Pasquier and Braguer, 2005)
We propose modes of binding interactions between nine benzimidazole-based drugs in comparison with the reference cocrystallized NZO drug (Figure 1) at colchicine binding site of tubulin protein
Crystallographic data of co-crystallized NZO complexed with tubulin protein (PDB: 5CA1) revealed the existence of two binding sites for NZO inside the protein, subunits B and D, TABLE 3 | Calculated hydrogen bond length between different benzimidazole drugs and NZO and the crucial amino acids at binding sites in subunits B and D of Tubulin protein

Summary

Introduction

Microtubules play a key role in the invasion and metastatic spread of tumor cells, depending on its crucial roles in mitosis, signaling, trafficking, proliferation, and migration of eukaryotic cells (Honore, Pasquier and Braguer, 2005). Drugs targeting microtubular proteins constitute a major and promising anticancer drug category exhibiting both antimitotic and antiangiogenic properties, besides inhibiting tumor progression in cancer and endothelial cells (D Katsetos and Draber, 2012). Colchicine binding site (CBS) is one of the five important identified binding sites on tubulin protein with the longest history of research as an anticancer target (Wang and Zhang, 2016). The success rate for new anticancer drugs from Phase I trial to commercial use by FDA approval is estimated to be around 6.7% from 2003 to 2011, taking about 8.3 years as an average There is a great global need for rapidly approved and effective anticancer drug candidates

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