连接器
肽
分子动力学
化学
环肽
胰蛋白酶
组合化学
配体(生物化学)
伞式取样
立体化学
生物物理学
计算化学
受体
生物化学
酶
计算机科学
生物
操作系统
作者
Lei Yu,Stephanie A. Barros,Chengzao Sun,Sandeep Somani
标识
DOI:10.1021/acs.jcim.3c01359
摘要
Cyclic peptides are an emerging therapeutic modality that can target protein-protein interaction sites with high affinity and selectivity. A common medicinal chemistry strategy for the optimization of peptide hits is conformational stabilization through macrocyclization. We present a method based on explicit solvent enhanced sampling molecular dynamics simulations for estimating the impact of varying linker lengths and chemistry on the conformational stability of a peptide. The method is demonstrated on three cyclic peptide series that bind to proteins PCSK9, trypsin, and MDM2 adopting loop, β-sheet, and helical secondary structures. In general, the simulations show greater solution stability of the receptor-bound conformation for the higher-affinity peptides, consistent with the idea that preorganizing a ligand for binding can enhance binding affinity. The impact of the force field and sampling is discussed for one series that does not follow this trend. We have successfully applied this method to internal discovery programs to design peptides with increased potency and chemical stability.
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