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Molecular modelling of quinoline derivatives as telomerase inhibitors through 3D-QSAR, molecular dynamics simulation, and molecular docking techniques

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Abstract

Rising mortality due to cancer has led to the development and identification of newer targets and molecules to cure the disease. Telomerase is one of the attractive targets for design of many chemotherapeutic drugs. This research highlights the designing of novel telomerase inhibitors using ligand-based (3D-QSAR) and structure-based (molecular docking and molecular dynamics simulation) approaches. For the development of the 3D-QSAR model, 37 synthetic molecules reported earlier as telomerase inhibitors were selected from diversified literature. Three different alignment methods were explored; among them, distill alignment was found to be the best method with good statistical results and was used for the generation of QSAR model. Statistically significant CoMSIA model with a correlation coefficient (r2ncv) value of 0.974, leave one out (q2) value of 0.662 and predicted correlation coefficient (r2pred) value of 0.560 was used for the analysis of QSAR. For the MDS study, A-chain of telomerase was stabilised for 50 ns with respect to 1-atm pressure, with an average temperature of 299.98 k and with potential energy of 1,145,336 kJ/m converged in 997 steps. Furthermore, the behaviour study of variants towards the target revealed that active variable gave better affinity without affecting amino acid sequences and dimensions of protein which was accomplished through RMSD, RMSF and Rg analysis. Results of molecular docking study supported the outcomes of QSAR contour maps as ligand showed similar interactions with surrounded amino acids which were identified in contour map analysis. The results of the comprehensive study might be proved valuable for the development of potent telomerase inhibitors.

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Acknowledgements

Authors are thankful to Nirma University, Ahmedabad, India, for supporting work, which is a part of Doctor of Philosophy (PhD) research work of Keerti Vishwakarma, to be submitted to Nirma University, Ahmedabad, India.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, India

    Keerti Vishwakarma & Hardik Bhatt

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  1. Keerti Vishwakarma
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Contributions

Keerti Vishwakarma: conceptualization; methodology and validation; data curation; writing—original draft

Hardik Bhatt: conceptualization; reviewing the methodology, results, and discussion; editing—final draft

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Correspondence to Hardik Bhatt.

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Supplementary information

ESM 1.

Supplementary Information file contains Field contributors of CoMSIA; Ramachandran plot of telomerase: (a) Plot of unsimulated protein structure; (b) Plot of simulated protein structure; Docking Score of potent molecules along with design compounds by Surflex docking module in SYBYL. (DOCX 853 kb)

ESM 2.

Mol 2 structures are also provided in zip file. (RAR 61.2 kb)

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Vishwakarma, K., Bhatt, H. Molecular modelling of quinoline derivatives as telomerase inhibitors through 3D-QSAR, molecular dynamics simulation, and molecular docking techniques. J Mol Model 27, 30 (2021). https://doi.org/10.1007/s00894-020-04648-2

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