Investigation of potential KRASG12D inhibitors: a comparative study between MRTX1133 and natural compounds via computational structural biology approaches

Two natural compounds, NPA019556 and NPA032945, demonstrated strong and stable binding interactions with KRASG12D, surpassing the performance of known inhibitor MRTX1133. After post-molecular dynamics analyses, which encompass Dynamic Cross-Correlation Matrix and Principal Component Analysis, additional evidence suggests that the flexible switch I (residues 30-40) and switch II (residues 58-72) regions demonstrate greater anti-correlation in NPA019556 and NPA032945 compared to MRTX1133 complexed with KRASG12D. These findings highlight the promise of two natural compounds, NPA019556 and NPA032945, as specific KRASG12D inhibitors, paving the way for future and therapeutic development.