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HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2′ Ligands To Optimize Hydrogen Bonding in the Substrate Envelope
- Source :
- J Med Chem
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- 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.
- Subjects :
- Models, Molecular
Anti-HIV Agents
Stereochemistry
medicine.medical_treatment
Stereoisomerism
Microbial Sensitivity Tests
Crystallography, X-Ray
Ligands
01 natural sciences
Article
Cell Line
Substrate Specificity
Structure-Activity Relationship
03 medical and health sciences
HIV Protease
HIV-1 protease
Drug Discovery
medicine
Humans
Moiety
Structure–activity relationship
Molecule
030304 developmental biology
0303 health sciences
Protease
Dose-Response Relationship, Drug
Molecular Structure
biology
Chemistry
Hydrogen bond
Diastereomer
Hydrogen Bonding
HIV Protease Inhibitors
0104 chemical sciences
010404 medicinal & biomolecular chemistry
HEK293 Cells
HIV-1
biology.protein
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....28fd17d85004f72f6d3054a61ca9e475