HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands to Optimize Hydrogen Bonding in the Substrate Envelope.
HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands to Optimize Hydrogen Bonding in the Substrate Envelope.
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DOI：
10.1021/acs.jmedchem.9b00838
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发表时间：
2019-08
影响因子：
7.3
通讯作者：
L. Rusere;G. J. Lockbaum;Sook-Kyung Lee;M. Henes;K. Kosovrasti;E. Spielvogel;E. Nalivaika;R. Swanstrom
中科院分区：
文献类型：
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作者：
L. Rusere;G. J. Lockbaum;Sook-Kyung Lee;M. Henes;K. Kosovrasti;E. Spielvogel;E. Nalivaika;R. Swanstrom
采用结构导向设计策略，通过优化氢键和与蛋白酶的货车范德华相互作用，同时保持在底物包膜内，来改善HIV-1蛋白酶抑制剂的耐药性。探索了4-（1-羟乙基）苯和4-（1，2-二羟乙基）苯部分的立体异构体作为P2'配体，提供了在P2'处差向异构的非对映异构体对，其根据羟基的构型和P1'基团的大小表现出不同的效力特征。虽然具有4-（1-羟乙基）苯P2'部分的化合物对一组多药耐药HIV-1菌株保持了优异的抗病毒效力，但具有极性4-（1，2-二羟乙基）苯部分的类似物效力较低，并且仅掺入较大的2-乙基丁基P1'基团的（R）-差向异构体显示出改善的效力。蛋白酶-抑制剂复合物的晶体结构揭示了羟乙基的（R）-和（S）-立体异构体与Asp 30 '的强氢键相互作用。值得注意的是，（R）-二羟乙基基团参与与Asp 29 '和Asp 30'的骨架酰胺的独特的直接氢键相互作用模式。SAR数据和晶体结构分析为优化这些有前途的HIV-1蛋白酶抑制剂提供了见解。
A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying within the substrate envelope. Stereoisomers of 4-(1-hydroxyethyl)benzene and 4-(1,2-dihydroxyethyl)benzene moieties were explored as P2' ligands providing pairs of diastereoisomers epimeric at P2', which exhibited distinct potency profiles depending on the configuration of the hydroxyl group and size of the P1' group. While compounds with the 4-(1-hydroxyethyl)benzene P2' moiety maintained excellent antiviral potency against a panel of multidrug-resistant HIV-1 strains, analogues with the polar 4-(1,2-dihydroxyethyl)benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1' group showed improved potency. Crystal structures of protease-inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30'. Notably, the (R)-dihydroxyethyl group was involved in a unique pattern of direct hydrogen bonding interactions with the backbone amides of Asp29' and Asp30'. The SAR data and analysis of crystal structures provide insights for optimizing these promising HIV-1 protease inhibitors.