Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK.
Eur J Med Chem. 2012 Aug;54:483-98. doi: 10.1016/j.ejmech.2012.05.034. Epub 2012 Jun 7.
S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand-protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines.
S-三苯甲基 L-半胱氨酸（STLC）是有丝分裂驱动蛋白 Eg5 的抑制剂，具有作为抗有丝分裂化疗药物的潜力。我们之前报道了配体-蛋白复合物的晶体结构，现在首次使用基于分子动力学的方法对相互作用进行了量化。基于这些数据，我们使用亚甲基洗牌策略探索了三苯甲基头部基团的 SAR，以扩大其中一个疏水口袋的占有率。最有效的化合物在基础 ATP 酶测定中对 Eg5 表现出强烈的抑制作用（<100 nM），并抑制多种肿瘤衍生细胞系的生长。
