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

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.

An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer

“…For this reason, K-Ras signaling could be taken as a perfect target in pancreatic cancer to offset the cancer continuation ( 49 ). KRAS is proposed as a significant therapeutic target, however, designing inhibitors against this potent therapeutic is challenging ( 47 , 50 ). The absence of binding pockets for drugs on KRAS protein, makes inhibitor designing a challenge ( 48 , 51 ).…”

“…Hence, most of the research in the past on targeting KRAS is focused on indirect approaches ( 46 ). Various drug designing strategies aiming at indirect targeting have been failed in the past ( 47 , 50 ). Because of that, direct targeting of RAS genes is reckoned feasible ( 50 ).…”

“…Various drug designing strategies aiming at indirect targeting have been failed in the past ( 47 , 50 ). Because of that, direct targeting of RAS genes is reckoned feasible ( 50 ). Lately, a new approach of direct covalent targeting of G12C mutant KRAS has revealed a potential dynamic binding pocket ( 48 , 51 ).…”

Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance

“…LB-CADD methods rather than SB-CADD procedures can also be used when the biologic target’s structure is unknown. Additionally, ligand-based virtual high-throughput screening (LB-vHTS) techniques frequently identify dynamic mixtures that are more potent than those identified by SB–vHTS [ 55 , 56 , 57 ].…”

Glimmers of hope for targeting oncogenic KRAS-G12D

“…Additional efforts are needed in the future to address basic and clinical questions to better optimize the activity of MRTX1133 and overcome its resistance. For example, how can this information from MRTX1133 be used to design KRAS-G12D covalent inhibitors [17]? Given that the animal experiments used in this study were immunodeficient mice, what are the effects of MRTX1133 treatment on the tumor immune microenvironment [18]?…”