Identification of New KRAS G12D Inhibitors through Computer-Aided Drug Discovery Methods.

Gihwan Lee,Sanghwa Yoon,Shraddha Parate,Apoorva M Kulkarni,Keun Woo Lee,Vikas Kumar

doi:10.3390/ijms23031309

Gihwan Lee, Sanghwa Yoon + Show 4 more

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https://doi.org/10.3390/ijms23031309

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Abstract

Owing to several mutations, the oncogene Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is activated in the majority of cancers, and targeting it has been pharmacologically challenging. In this study, using an in silico approach comprised of pharmacophore modeling, molecular docking, and molecular dynamics simulations, potential KRAS G12D inhibitors were investigated. A ligand-based common feature pharmacophore model was generated to identify the framework necessary for effective KRAS inhibition. The chemical features in the selected pharmacophore model comprised two hydrogen bond donors, one hydrogen bond acceptor, two aromatic rings and one hydrophobic feature. This model was used for screening in excess of 214,000 compounds from InterBioScreen (IBS) and ZINC databases. Eighteen compounds from the IBS and ten from the ZINC database mapped onto the pharmacophore model and were subjected to molecular docking. Molecular docking results highlighted a higher affinity of four hit compounds towards KRAS G12D in comparison to the reference inhibitor, BI-2852. Sequential molecular dynamics (MD) simulation studies revealed all four hit compounds them possess higher KRAS G12D binding free energy and demonstrate stable polar interaction with key residues. Further, Principal Component Analysis (PCA) analysis of the hit compounds in complex with KRAS G12D also indicated stability. Overall, the research undertaken provides strong support for further in vitro testing of these newly identified KRAS G12D inhibitors, particularly Hit1 and Hit2.

Highlights

The transition from active to inactive form involves the changes in the conformation which is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) [1]
G12D inhibitors reported by Kessler et al [3], we first discerned the important chemical
A common feature pharmacophore model was generated to extract the important features for Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibition

Summary

Introduction

The chemical features in the selected pharmacophore model comprised two hydrogen bond donors, one hydrogen bond acceptor, two aromatic rings and one hydrophobic feature. This model was used for screening in excess of 214,000 compounds from InterBioScreen (IBS). 1. Introduction with regard to jurisdictional claims in RAS genes (KRAS, HRAS, and NRAS) belong to the RAS family of small GTPases. Introduction with regard to jurisdictional claims in RAS genes (KRAS, HRAS, and NRAS) belong to the RAS family of small GTPases They cycle between an active GTP-bound state and an inactive GDP-bound state, and function as molecular switches, depending on extracellular signals.

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