Scholarlink

<p>Modeling non-covalent inhibitors of RAS oncoproteins has so far been carried out at whole molecule level, which left important molecular details hidden. Actually, for the endless process of improving the inhibitor performance, a more detailed knowledge of such interactions is desirable. The challenge has been taken in this work by disentangling the energies of interaction of KRAS-G12D-mutant residues with non-covalent inhibitors that, such as BI-2865 and MRTX1133, are currently on the limelight. In the lack of suitable experimental methodologies, the task has been addressed to molecular dynamics and quantum mechanics-molecular mechanics computer simulations. It emerged where, quantitatively at residue level, the inhibitor sticks better and where destabilizing repulsions arise. Moreover, for the newly appeared ternary complex of the non-covalent inhibitor RCM-6236 with cyclophilin A and KRAS G12R, a similar analysis gave also hints as to the mechanism of inhibition. Such detailed views offer clues as to improving the structure of the next generation non-covalent KRAS inhibitors.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Disentangling the non-bonding interaction energy between KRAS oncoproteins and small-molecule non-covalent inhibitors helps clarifying how inhibition occurs

  • 期刊论文

  • 发表日期：

    2025年11月19日

查看全文
  • Francesco Pietra

摘要

Modeling non-covalent inhibitors of RAS oncoproteins has so far been carried out at whole molecule level, which left important molecular details hidden. Actually, for the endless process of improving the inhibitor performance, a more detailed knowledge of such interactions is desirable. The challenge has been taken in this work by disentangling the energies of interaction of KRAS-G12D-mutant residues with non-covalent inhibitors that, such as BI-2865 and MRTX1133, are currently on the limelight. In the lack of suitable experimental methodologies, the task has been addressed to molecular dynamics and quantum mechanics-molecular mechanics computer simulations. It emerged where, quantitatively at residue level, the inhibitor sticks better and where destabilizing repulsions arise. Moreover, for the newly appeared ternary complex of the non-covalent inhibitor RCM-6236 with cyclophilin A and KRAS G12R, a similar analysis gave also hints as to the mechanism of inhibition. Such detailed views offer clues as to improving the structure of the next generation non-covalent KRAS inhibitors.