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

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-1 alpha inhibitor via interaction with key residues of the HIF-1 alpha active site. Taking into consideration the role HIF-1 alpha in cancer and potency of indazole derivative against HIF-1 alpha; it was considered of interest to correlate structural features of known indazole derivatives with specified HIF-1 alpha 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-1 alpha 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 (A(1)D(2)R(3)R(4)R(5)_4) which can be employed in combination with 3D-contour maps to design potent HIF-1 alpha 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-1 alpha 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-1 alpha inhibitors for the treatment of Cancer.

Automated summary

This study investigated the pharmacophoric features and inhibitory potency of HIF-1 alpha inhibitors through three-dimensional quantitative structural activity relationship and pharmacophore mapping. It was found that indazole derivatives have the potential to be effective inhibitors of HIF-1 alpha, and molecular docking and molecular dynamics simulations confirmed the binding efficiency and stability of the most potent compound. The developed models and analysis techniques can be used to design selective lead molecules for the treatment of cancer.