CAJ | 학술논문

含有锍离子的葡萄糖苷酶抑制剂如kotalanol (SK)和它除去磺酸基团后的衍生物(DSK),是潜在的毒副作用较小的治疗Ⅱ型糖尿病的候选药物.α-葡萄糖苷酶抑制活性实验显示,DSK活性比SK略高,而将二者环上的S原子替换成NH后(分别称为DSN和SN),DSN的活性要比SN高1500倍左右.本文用分子动力学模拟,结合自由能计算和自由能分解的方法对上述四个抑制剂的作用机理进行了研究.研究结果表明活性的巨大差异是由NH基团取代效应和磺酸基团立体效应共同作用的结果,由于N—C键长比S—C键长短,NH基团取代导致烷基链的翻转,同时,磺酸基团限制了链的翻转,因此改变了抑制剂的结合模式.计算结果与实验基本一致.本文的研究结果有助于进一步理解含锍离子的葡萄糖苷酶抑制剂的结合机理,并为设计更有潜力的葡萄糖苷酶抑制剂提供了有价值的信息.
함유류리자적포도당감매억제제여kotalanol (SK)화타제거광산기단후적연생물(DSK),시잠재적독부작용교소적치료Ⅱ형당뇨병적후선약물.α-포도당감매억제활성실험현시,DSK활성비SK략고,이장이자배상적S원자체환성NH후(분별칭위DSN화SN),DSN적활성요비SN고1500배좌우.본문용분자동역학모의,결합자유능계산화자유능분해적방법대상술사개억제제적작용궤리진행료연구.연구결과표명활성적거대차이시유NH기단취대효응화광산기단입체효응공동작용적결과,유우N—C건장비S—C건장단,NH기단취대도치완기련적번전,동시,광산기단한제료련적번전,인차개변료억제제적결합모식.계산결과여실험기본일치.본문적연구결과유조우진일보리해함류리자적포도당감매억제제적결합궤리,병위설계경유잠력적포도당감매억제제제공료유개치적신식.
Sulfonium ion glucosidase inhibitors such as kotalanol (SK) and de-O-sulfonated kotalanol (DSK) are potential drug candidates for the treatment of type Ⅱ diabetes,with no serious toxicity or side effects.Experimental binding assays against glucosidase show that the activity of DSK is slightly higher than that of SK,while the activity of the nitrogen analogue of de-O-sulfonated kotalanol (DSN) is ～1500-fold higher than that of the nitrogen analog of kotalanol (SN).Here,the binding mechanisms of four representative inhibitors of glucoamylase,SK,DSK,and their two nitrogen analogues,were explored in an integrated modeling study combining molecular dynamics (MD) simulations,binding free energy calculations,and binding free energy decomposition analysis.Our simulations highlight the significant impact of the combination of nitrogen substitution and sulfate anion group.Nitrogen substitution in the five-membered ring leads to the overturning of the polyhydroxylated chain,originating from the shorter bond length of N — C compared with S — C,while the sulfate anion group restrains the freedom of the polyhydroxylated chain.These cumulative effects are able to significantly change the binding conformation of the inhibitor and substantially impair interactions between the inhibitor and glucosidase.The structural insights obtained in this study are expected to be valuable for increased understanding of the binding mechanism of sulfonium ion glucosidase inhibitors and future design of more potent glucosidase inhibitors.