FDA approved fused-pyrimidines as potential PI3K inhibitors: a computational repurposing approach

Abstract

Fused pyrimidine scaffold is present in several US FDA-approved drugs for various therapeutic indications. Drug repurposing (or drug repositioning) involves the analysis of existing clinically approved drugs for new therapeutic indications. Phosphoinositide-3-kinase (PI3K), via the regulatory PI3K pathway, is involved in cell growth, proliferation, differentiation, survival, and angiogenesis. It is also considered a target in anticancer drug development as it promotes the growth of cancerous cells and increases resistance to anticancer therapy. The present work employed computational techniques like molecular docking, MMGBSA analysis, and molecular dynamics simulations to explore the PI3K inhibition by FDA-approved drugs with fused pyrimidine scaffold. The work identifies Lapatinib as a pan-class I PI3K inhibitor and Dipyridamole as an γ isoform-specific PI3K inhibitor and is reported here.