Unveiling KRAS G12D inhibition: from molecular dynamics to therapeutic strategies

Addressing the KRAS G12D mutation, a common driver in various cancers, remains a formidable challenge in targeted therapy development. In our study, we performed an extensive molecular dynamics simulation totaling 12 μs across several protein–ligand complexes to uncover the most promising inhibitors against this mutation. Among experimental candidates, THZ835, MTRX1133 and THZ816–THZ835 stood out, exhibiting exceptional stability and binding energy within the KRAS G12D switch II pocket at an atomistic level. This robust performance established THZ835 as the pharmacophore model for our subsequent structure-based drug design. Furthermore, our virtual screening identified structurally similar compounds, notably CID₁46527942 and CID₁32145180, which demonstrated binding affinities comparable to THZ835. Intriguingly, our analysis suggests that the enhanced binding efficacy of CID₁46527942 may be attributed to the formation of salt bridges with key residues such as Asp12 in KRAS G12D, adding a novel dimension to our understanding of stabilizing factors within the binding pocket, while THZ835′s efficacy likely stems from other interactions. While THZ835 exhibited the highest binding affinity, the potential of CID₁46527942 and CID₁32145180 as alternative inhibitors highlights the importance of considering diverse interaction dynamics in drug efficacy. Overall, our study, leveraging a 12-μs MD simulation and detailed molecular interaction analysis, lays the groundwork for innovative therapeutic strategies targeting KRAS G12D-mutant cancers.