Liesen Michael P, Hayes Ryan L, Brooks Iii Charles L, Vilseck Jonah Z
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
J Phys Chem Lett. 2025 Jun 26;16(25):6273-6278. doi: 10.1021/acs.jpclett.5c00467. Epub 2025 Jun 12.
Though commonly used in drug discovery, alchemical free energy calculations have not been extensively used to explore issues of drug resistance caused by missense mutations to a drug target. Unlike traditional methods, λ-dynamics (λD) can evaluate multiple modifications within a single simulation; however, perturbations on more than one molecule, e.g., in a ligand and receptor, have not been performed previously. In an approach referred to as Multiple Molecule λ-Dynamics (MMλD), simultaneous ligand and protein perturbations are performed in a single simulation to sample a small series of ligands bound to native and T315I mutant Abl kinases, a protein target in chronic myelogenous leukemia associated with drug resistance. MMλD agreement with conventional λD calculations and experiments is high, with mean unsigned errors of 0.21 and 0.94 kcal/mol, respectively. Protein sequence specific ligand conformational sampling is also identified. Collectively, this work demonstrates that MMλD is a valuable tool for drug resistance drug discovery.
尽管炼金术自由能计算在药物发现中常用，但尚未广泛用于探索由药物靶点错义突变引起的耐药性问题。与传统方法不同，λ动力学（λD）可以在单个模拟中评估多个修饰；然而，此前尚未对一个以上分子（例如配体和受体）进行扰动。在一种称为多分子λ动力学（MMλD）的方法中，在单个模拟中同时对配体和蛋白质进行扰动，以对与天然和T315I突变体Abl激酶（慢性粒细胞白血病中与耐药性相关的一种蛋白质靶点）结合的一小系列配体进行采样。MMλD与传统λD计算和实验的一致性很高，平均无符号误差分别为0.21和0.94千卡/摩尔。还确定了蛋白质序列特异性配体构象采样。总体而言，这项工作表明MMλD是耐药性药物发现的一个有价值的工具。
