Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring
Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring
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DOI：
10.1021/jm300072d
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Weber, Irene T.
中科院分区：
文献类型：
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作者：
Chang, Yu-Chung E.;Yu, XiaXia;Weber, Irene T.
GRL-02031（1）是一种HIV-1蛋白酶（PR）抑制剂，含有一个新的P1'（R）-氨甲基-2-吡咯烷酮基团。在1.25-1.55埃的分辨率下分析1与含有主要耐药突变PRI 47 V、PRL 76 V、PRV 82 A和PRN 88 D的PR的复合物的晶体结构。I47 V和V82 A的突变改变了抑制剂结合位点的残基，而L76 V和N88 D是与抑制剂没有直接接触的远端突变。与野生型PR相比，PRI 47 V和PRL 76 V中较小氨基酸的取代和PRN 88 D电荷的改变与显著的局部结构变化相关，而PRV 82 A中丙氨酸的取代增加了S1'亚位点的大小。1的P1'吡咯烷酮基团通过假设两种不同的构象来适应这些局部变化。总体而言，1与PR突变体的构象和相互作用类似于PRWT，具有相似的抑制常数，与对多药耐药HIV-1的抗病毒效力非常一致。
GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 angstrom were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PRI47V, PRL76V, PRV82A, and PRN88D. Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PRI47V and PRL76V and the altered charge of PRN88D are associated with significant local structural changes compared to the wild-type PR, while substitution of alanine in PRV82A, increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PRWT with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.