CAJ | 학술논문

作为第二代共价类蛋白酶体抑制剂,硼酸肽类抑制剂由于代谢稳定,且具较高的蛋白酶体抑制活性和选择特异性,已成为当前新型抗肿瘤药物的重点研究内容.本文以最近合成的44个 Tyropeptin 硼酸三肽类蛋白酶体抑制剂为研究对象,采用共价距离约束,对该类分子与蛋白酶体进行了分子对接研究.结果表明,该类抑制剂与蛋白酶体的非共价相互作用主要以氢键和疏水作用为主,具体表现为:(1)硼酸基团的羟基与ARG19、LYS33和 GLY47的氢键作用;(2)肽链骨架原子与 THR21、GLY47和 ALA49的氢键作用;(3)R1基团与 S1口袋的疏水作用和氢键作用.基于对接构象,对上述分子进行了骨架叠合及随后的比较分子场分析(CoMFA)和比较分子相似性形状指数分析(CoMSIA).最优模型为包含氢键供体场、疏水场、氢键受体场以及立体场的 CoMSIA 模型,其最佳主成分数、决定系数 r2、标准差 S、交互验证系数 q2以及外部预测 r2pred 分别为3、0.882、0.188、0.494以及0.756.在以上研究基础上,以活性最高的3C 和6号分子为模板,采用基于遗传算法的结构搜索方法,结合分子相似性评价函数,对其侧链进行了优化设计.结合 Lipinski“5规则”和最优 CoMSIA 模型活性预测结果,最终得到5个目标分子,其预测活性均达到纳摩尔水平.
작위제이대공개류단백매체억제제,붕산태류억제제유우대사은정,차구교고적단백매체억제활성화선택특이성,이성위당전신형항종류약물적중점연구내용.본문이최근합성적44개 Tyropeptin 붕산삼태류단백매체억제제위연구대상,채용공개거리약속,대해류분자여단백매체진행료분자대접연구.결과표명,해류억제제여단백매체적비공개상호작용주요이경건화소수작용위주,구체표현위:(1)붕산기단적간기여ARG19、LYS33화 GLY47적경건작용;(2)태련골가원자여 THR21、GLY47화 ALA49적경건작용;(3)R1기단여 S1구대적소수작용화경건작용.기우대접구상,대상술분자진행료골가첩합급수후적비교분자장분석(CoMFA)화비교분자상사성형상지수분석(CoMSIA).최우모형위포함경건공체장、소수장、경건수체장이급입체장적 CoMSIA 모형,기최가주성분수、결정계수 r2、표준차 S、교호험증계수 q2이급외부예측 r2pred 분별위3、0.882、0.188、0.494이급0.756.재이상연구기출상,이활성최고적3C 화6호분자위모판,채용기우유전산법적결구수색방법,결합분자상사성평개함수,대기측련진행료우화설계.결합 Lipinski“5규칙”화최우 CoMSIA 모형활성예측결과,최종득도5개목표분자,기예측활성균체도납마이수평.
Recently, as the second generation of 20S proteasome inhibitors, peptide boronic acid derivatives have received much more attentions due to its stable metabolism, strong inhibitory activity, high specificity, and low toxicity. However, the structures of proteasome inhibitors are relatively complex and flexible, which causes troubles for structure-based drug design. In this paper, molecular docking was applied to mechanism study on 44 boronic acid derivatives of tyropeptin inhibitors of 20S proteasome. The results showed that main non-covalent interactions between boronic acid derivatives of tyropeptin and proteasome are as follows: (1) H-bond interactions between OH of boronic acid group and ARG19, LYS33, and GLY47; (2) H-bond interactions between atoms of backbone of peptide and THR21, GLY47, and ALA49; (3) Hydrophobic and H-bond interactions between R1 group and S1 pocket of proteasome. Based on the docking conformers, all 44 samples were aligned according to the sketch atoms and then used for following CoMFA and CoMSIA To obtain the optimal CoMSIA model, of which the number of principal component, determination coefficients (r2), standard deviation (S), cross-validated r2 (q2), and determination coefficients for external samples (r2pred) of were 3, 0.882, 0.188, 0.494 and 0.756, respectively. Then, de novo molecular design was performed based on 2 templates with high activities. GA-based structure search algorism and similarity evaluation function was used to guide the evolution process. Five new molecules were obtained according to the rule of Lipinski and as- predicted activities by the optimal CoMSIA model. The inhibitory activities of them are all at nano level.