Identification of potential inhibitors of hypoxanthine-guanine phosphoribosyl transferase for cancer treatment by molecular docking, dynamics simulation and in vitro studies

Hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1) is a mutational biomarker and a housekeeping human reporter gene that is predominantly employed to assess mutation frequencies associated with cancer development. In this study, our purpose was to identify potential inhibitors against the human hypoxanthine guanine phosphoribosyltransferase (HPRT) protein encoded by HPRT1 gene by employing an integrated in silico approach. The library of 17,967 phytochemicals (IMPPAT 2.0 database) was screened for drug-like properties followed by molecular docking, resulting in the selection of top 20 phytochemicals. Further interaction profile revealed that IMPHY008718 (Gibberellin A34) and IMPHY011650 (Chasmanthin) binds at the GMP binding site of the HPRT1 protein. ADMET properties and biological function predictions of the selected compounds indicate their anticancer potential. Both IMPHY008718 and IMPHY011650 docked complexes were examined in 200 ns MD simulations. Comprehensive MD trajectory analysis was performed in addition to principal component, free energy and MM/PBSA analysis. Furthermore, in vitro human HPRT inhibition assay confirmed and revealed inhibitory potential for Gibberellin A34 (<i>K</i>_i 0.121 µM) and Chasmanthin (<i>K</i>_i 0.368 µM), as compared to standard inhibitor, HGPRT/TBrHGPRT1-IN-1 (<i>K</i>_i 0.032 µM). Overall, these results strongly recommend further experimental work concerning these plant-based molecules as human HPRT inhibitors for anticancer drug development.