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Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Dec 08; Vol. 65 (23), pp. 15608-15626. Date of Electronic Publication: 2022 Nov 21. - Publication Year :
- 2022
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Abstract
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them, 36a exhibited outstanding antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC <subscript>50</subscript> ranging from 2.22 to 53.3 nM. Besides, 36a was identified with higher binding affinity ( K <subscript>D</subscript> = 2.50 μM) and inhibitory activity (IC <subscript>50</subscript> = 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally, 36a·HCl exhibited favorable PK ( T <subscript>1/2</subscript> = 5.12 h, F = 12.1%) and safety properties (LD <subscript>50</subscript> > 2000 mg/kg). All these suggested that 36a·HCl may serve as a novel drug candidate anti-HIV-1 therapy.
- Subjects :
- Molecular Docking Simulation
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36411036
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c00576