Molecular dynamics and 3D-QSAR studies on indazole derivatives as HIF-1α inhibitors

Abstract

Hypoxia-inducible factor (HIF) is a transcriptional factor which plays a crucial role in tumour metastasis thereby responsible for development of various forms of cancers. Indazole derivatives have been reported in the literature as potent HIF-1α inhibitor via interaction with key residues of the HIF-1α active site. Taking into consideration the role HIF-1α in cancer and potency of indazole derivative against HIF-1α; it was considered of interest to correlate structural features of known indazole derivatives with specified HIF-1α inhibitory activity to map pharmacophoric features through Three-dimensional quantitative structural activity relationship (3D-QSAR) and pharmacophore mapping. Field and Gaussian based 3D-QSAR studies were performed to realize the variables influencing the inhibitory potency of HIF-1α inhibitors. Field and Gaussian- based 3D-QSAR models were validated through various statistical measures generated by partial least square (PLS). The steric and electrostatic maps generated for both 3D-QSAR provide a structural framework for designing new inhibitors. Further; 3D-maps were also helpful in understanding variability in the activity of the compounds. Pharmacophore mapping also generates a common five-point pharmacophore hypothesis (A₁D₂R₃R₄R₅_4) which can be employed in combination with 3D-contour maps to design potent HIF-1α inhibitors. Molecular docking and molecular dynamics (MD) simulation of the most potent compound 39 showed good binding efficiency and was found to be quite stable in the active site of the HIF-1α protein. The developed 3D-QSAR models; pharmacophore modelling; molecular docking studies along with the MD simulation analysis may be employed to design lead molecule as selective HIF-1α inhibitors for the treatment of Cancer.

KEYWORDS::

• Cancer;
• HIF-1α inhibitor
• drug design
• pharmacophore
• 3D-QSAR
• MD simulation

Acknowledgements

Yogesh is grateful to All India Council for Technical Education (AICTE) for providing GPAT fellowship. Author`s acknowledges Department of Science and Technology (DST) for providing the Departmental DST-FIST grant (SR/FST/LSI-656/2016) to the Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, India.

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Disclosure statement

The authors declare that they have no conflict of interest. S.T conceptualized the present research. The computational methodology and formal analysis were performed by Y.S., K.S.S. and P.K. MD simulation and analysis were performed by S.S. and Y.S. The interpretation of all the results and original draft of manuscript was prepared by S.T., P.K., Y.S. and K.S.S.

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The author(s) reported there is no funding associated with the work featured in this article.

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