Journal article
"Pseudosubstrate Envelope"/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency
Journal of medicinal chemistry, v 67(21), pp 19057-19076
14 Nov 2024
PMID: 39418501
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Based on our proposed "pseudosubstrate envelope" concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, IC-1k, exhibited an EC50 of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, IC-1k emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that IC-1k targeted HIV-1 CA within the chemical space of the "pseudosubstrate envelope". Further mechanistic studies revealed a dual-stage inhibition profile: IC-1k disrupted early-stage capsid-host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for IC-1k (T- 1/2 = 91.3 min) compared to PF74 (T (1/2) = 0.7 min), alongside a favorable safety profile. Overall, IC-1k presents a promising lead compound for further optimization.
Metrics
Details
- Title
- "Pseudosubstrate Envelope"/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency
- Creators
- Shujing Xu - Shandong UniversityShuo Wang - Shandong UniversityYang Zhou - Shandong UniversityNicholas Foley - Drexel UniversityLin Sun - Shandong UniversityLaura Walsham - University of AucklandKai Tang - Shandong UniversityDazhou Shi - Shandong UniversityXiaoyu Shi - Shandong UniversityZhijiao Zhang - Shandong UniversityXiangyi Jiang - Shandong UniversityShenghua Gao - Shandong UniversityXinyong Liu - Shandong UniversityChristophe Pannecouque (Corresponding Author) - Rega Institute for Medical ResearchDavid C. Goldstone (Corresponding Author) - University of AucklandAlexej Dick (Corresponding Author) - Drexel University, Biochemistry and Molecular BiologyPeng Zhan (Corresponding Author) - Shandong University
- Publication Details
- Journal of medicinal chemistry, v 67(21), pp 19057-19076
- Publisher
- Amer Chemical Soc
- Number of pages
- 20
- Grant note
- 900048 / NINDS HIV-1 Tat genetic Variation I SYS202205 / Shandong Laboratory Program 2023YFC2606500 / Ministry of Science and Technology of the People's Republic of China; Ministry of Science and Technology, China 284247 / Coulter Foundation 82173677 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) R01AI150491 / NIH/NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001337695400001
- Scopus ID
- 2-s2.0-85207882114
- Other Identifier
- 991021929987604721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal