分子对接与分子动力学模拟法探究PI3Kδ/度维利塞(Duvelisib)的选择性结合

Theoretical studies on the selectively binding mechanism of PI3Kδ/Duvelisib based on molecular docking and molecular dynamic simulations

大量研究表明磷脂酰肌醇3-激酶δ(PI3Kδ)与多种恶性肿瘤及免疫疾病的发生、发展密切相关,因此成为一个备受关注的药物靶点。伊德利塞(Idelalisib),PI3Kδ抑制剂,是首个被FDA批准上市的PI3K抑制剂,以此开启了PI3Kδ选择性抑制剂开发的热潮,但是严重的毒副作用阻碍了该类化合物的使用。随后,度维利塞(Duvelisib,IPI-145)于2018年被批准上市,度维利塞是PI3Kδ/γ选择性抑制剂,然而目前关于度维利塞的选择性PI3K抑制分子机制报道较少,且目前尚无度维利塞/PI3K复合物晶体结构报道。因此本文采用整合的计算机模拟策略来揭示度维利塞的选择性抑制机制:通过分子对接获得度维利塞与PI3K各亚型的合理结合构象;分子动力学模拟结合自由能计算揭示选择性产生的关键位点及热点氨基酸。目前,因与其他亚型之间高度的同源性与结构保守性,使得PI3Kδ选择性抑制剂开发受到极大挑战,本文以上市药物度维利塞为研究主体,有望为新型PI3Kδ选择性抑制剂的开发及合理药物设计提供一定的指导意义。

A large number of studies have demonstrated that phosphoinositide 3-kinase delta(PI3Kδ)is closely related to the occurrence and development of various malignant tumors and immune diseases,so it has become an attractive drug target.Idelalisib,a PI3Kδinhibitor,is the first PI3K inhibitor approved by the FDA.The successful development of Idelalisib opens the door to discover lots of specific PI3K inhibitors.However,serious toxic and side effects hinder the use of Idelalisib.Subsequently,Duvelisib(IPI-145)was approved for marketing in 2018.IPI-145 is a selective inhibitor of PI3Kδ/γ.However,there are few reports on the molecular mechanism of IPI-145 selectivity,and there is no crystal structure of IPI-145/PI3K complex being reported.Therefore,in this research,we utilized an integrated strategy based on computer simulations to reveal the selective inhibition mechanism of IPI-145:the reasonable binding conformation of IPI-145 with each PI3K isoform is obtained through molecular docking;molecular dynamics simulation combined with free energy calculation reveals the key sites and hotspot amino acids related to selectivity.Currently,due to the highly sequential homology and structural similarity among PI3Ks,developing PI3Kδselective inhibitors is a challenging endeavor.In this paper,the marketed drug IPI-145 was chosen as a molecular tool,and it would provide guidance for the discovery or rational design of novel specific PI3Kδinhibitors.