化学
药效团
螺旋(腹足类)
小分子
合作性
氨基酸
组合化学
热点(计算机编程)
分子
立体化学
生物化学
计算机科学
有机化学
蜗牛
生态学
操作系统
生物
标识
DOI:10.1021/acs.jcim.1c01556
摘要
The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand-protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein-protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein-protein binding conformation convergence of hydrophilic α-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic α-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic α-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type α-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic α-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of α-helix mimetics.
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