3D-QSAR study, docking molecular and simulation dynamic on series of benzimidazole derivatives as anti-cancer agents

Abstract

Benzimidazole is an important heterocyclic organic compound which has a structural analogy to nucleotides found in human body and hence is an important pharmacophore in medicinal chemistry. The anti-cancer activities for a diverse set of benzimidazole as anti-cancer agents against breast cancer cell line (MCF7) assay have been subjected to 3D-QSAR (3-Dimensional Quantitative Structural-Activity Relationship) studies. Both CoMFA and CoMSIA models exhibit significant results in terms of statistical parameters as determination coefficients R2 > 0.9 and Leave One Out cross-validation determination coefficients Q2> 6. The predictive quality of both 3D QSAR models have been assessed by external validation and Y-randomization test. Five new compounds have been designed and predicted by in silico ADMET method. In the second part, we have used the docking molecular and simulation dynamics (MD) to investigate the bonding interactions and stability of the designed compounds into the Pin1. Then, we have compared them to Trastuzumab and Tamoxifen as a standard inhibitors drug of breast cancer. The designed compounds form stable hydrogen and hydrophobic bonding interactions with the residues Lys63, Gln131, Ser154, Arg 68 and Arg69 of Pin1 receptor during 100 ns as a time of the simulation. The obtained results showed that the new benzimidazole are useful as a template for future design of more potent inhibitors against breast cancer cell lines (MCF7).