3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents

Abstract

Insulin like growth factor receptor (IGF-1R) and Insulin receptor (IR) are widely accepted to play a prominent role in cancer drug discovery due to their well-established involvement in various stages of tumorigenesis. Previously, neutralization of IGF-1R via monoclonal antibodies was in focus, which failed because of compensatory activation of IR-A upon inhibition of IGF-1R. Recent studies have demonstrated high homology between IGF-IR and IR particularly in tyrosine kinase domain and targeting both receptors have produced efficient therapeutic approaches such as inhibition of cancer cell cycle proliferation. Herein, we have made an attempt to analyze the unique data set from different chemical classes, containing potent ATP competitors against tyrosine kinase domain. We performed the 2D, 3D quantitative structure–activity relationship (QSAR) studies on inhibitors of these receptors to predict useful pharmacophoric features. We have optimized virtual screening of structurally diverse data set of dual inhibitors of IGF-1R and IR. Based on QSAR studies, we predict potential novel clinical candidates with a demonstrated absorption, distribution, metabolism, elimination, and toxicology (ADMETox) track. We also demonstrated comprehensive analysis of co–crystal complexes along with their inhibitors and built 3D- GRid INdependent Descriptors (GRIND) model to obtain insightful features such as H-bond donors and acceptors, overall topology and Vander Waal volume (vdw_vol) which are found to be responsible for dual inhibition of receptors. These findings lead to further description that Tirofiban, Practolol, Edoxaban, Novobiocin have potential to perform dual inhibition of both targets. • Monoclonal antibodies to neutralise IGF-1R failed due to activation of IR upon IGF-1R inhibition leading. • The study focuses on ATP competitive ligands from different chemicals classes against tyrosine kinase using 2D and 3D QSAR. • Our study predicts Tirofiban, Practolol, Edoxaban and Novobiocin as potential novel candidates for dual inhibition. • We cross validated these ligands by building additional pharmacophores which confirmed the Mathew's correlation at 79%.