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Mechanistic insights into KRASG12D inhibitor binding revealed by molecular dynamics simulations of multiple crystal
Donghwan Kim1, Eunho Lee1, Sangbae Lee1
1Atomatrix, 851, Daewangpangyo-ro 815, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea. sblee@atomatrix.co.kr.
Abstract:
The discovery of selective and potent KRASG12D inhibitors remains a critical priority in oncology drug development. Here, we performed comparative all-atom molecular dynamics (MD) simulations on four KRASG12D-inhibitor complexes (PDB IDs: 7RPZ, 7RT2, 7EWB, 7EW9) spanning a wide affinity range (IC50 = 2 nM-14 µM). By integrating high-resolution crystallographic data with ex-tensive all-atom MD simulations, we aimed to elucidate the structural and dynamic determinants that differentiate high- and low-affinity inhibitor binding. Alchemical free-energy calculations yielded ΔG values of -11.3 to -6.2 kcal mol-1, which showed a strong correlation with experimental pIC50 (R2 = 0.92). Per-residue energy decomposition revealed five dominant polar interaction hotspots (D12 ≈ -34, G60 ≈ -13, E62 ≈ -20, D69 ≈ -17, and D92 ≈ -6 kcal mol-1) driving stable bind- ing, whereas weak inhibitors exhibited markedly reduced contributions at these residues. Structural dynamics analysis further showed that strong binders maintained compact binding pockets (RMSD: 1.8-2.2 Å) and reduced ligand flexibility, whereas weak binders sampled expanded and less stable conformations (RMSD: 2.7-3.4 Å). These findings delineate the structural and energetic determinants underlying KRASG12D inhibitor potency and provide quantitative guidelines for the rational design of next-generation KRASG12D inhibitors.
Insights
Developing potent KRASG12D inhibitors is crucial for cancer therapy. Molecular dynamics simulations reveal key structural and dynamic factors, including specific polar interactions and binding pocket stability, that differentiate high-affinity KRASG12D inhibitors from low-affinity ones.
Area of Science:
- Oncology
- Computational Chemistry
- Structural Biology
Background:
- Targeting KRASG12D is a significant challenge in cancer drug development.
- Selective and potent KRASG12D inhibitors are urgently needed for effective cancer treatment.
Purpose of the Study:
- To elucidate the structural and dynamic factors distinguishing high- and low-affinity KRASG12D inhibitors.
- To provide quantitative insights for designing next-generation KRASG12D inhibitors.
Main Methods:
- Comparative all-atom molecular dynamics (MD) simulations of four KRASG12D-inhibitor complexes.
- Integration of crystallographic data with MD simulations.
- Alchemical free-energy calculations and per-residue energy decomposition.
Main Results:
- Strong correlation (R2 = 0.92) between calculated free energies and experimental pIC50 values.
- Identification of five dominant polar interaction hotspots (D12, G60, E62, D69, D92) crucial for stable binding.
- Strong binders exhibited compact, stable binding pockets (RMSD: 1.8-2.2 Å) and reduced ligand flexibility, unlike weak binders (RMSD: 2.7-3.4 Å).
Conclusions:
- Specific polar interactions and binding pocket dynamics are critical determinants of KRASG12D inhibitor potency.
- These findings offer quantitative guidelines for the rational design of improved KRASG12D inhibitors.
- The study advances the development of targeted cancer therapies by understanding inhibitor-target interactions at a molecular level.
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