Journal article
Computational Evaluation of HIV-1 gp120 Conformations of Soluble Trimeric gp140 Structures as Targets for de Novo Docking of First- and Second-Generation Small-Molecule CD4 Mimics
Journal of chemical information and modeling, v 56(10), pp 2069-2079
24 Oct 2016
PMID: 27602436
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Small-molecule CD4 mimics (SMCM’s) bind to the gp120 subunit of the HIV-1 envelope glycoprotein (Env) and have been optimized to block cell infection in vitro. The lack of the V1/2 and V3 loops and the presence of the β2/3 and β20/21 strands (bridging sheet) in the available structures of the monomeric gp120 core may limit its applicability as a target for further synthetic optimization of SMCM potency and/or breadth. Here, we employ a combination of binding-site search, docking, estimation of protein–ligand interaction energy, all-atom molecular dynamics, and ELISA-based CD4-binding competition assays to create, characterize, and rationalize models of first- and second-generation of SMCM’s bound to the distinct, trimeric BG505 SOSIP.664 structures 4NCO and 4TVP containing V1/2 and V3 loops with no bridging sheet. We demonstrate that the in silico neutralization of the highly conserved D368 is necessary to obtain the correct orientation of SMCM in their binding site when docking against the monomeric gp120 core. The computational results correlate with IC
50
’s measured in CD4 binding competition ELISA and with
K
D
’s measured on gp120 core monomer. This supports the hypothesis that the 4NCO trimeric structure represents a viable target for further SMCM’s optimization with advantages over both the 4TVP trimer and gp120 core monomer. Finally, the docking protocol has been optimized to screen compounds that can clearly interact with the highly conserved residue D368, increasing the likelihood of future optimizations to arrive at SMCM’s with a broader spectrum of activity.
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Details
- Title
- Computational Evaluation of HIV-1 gp120 Conformations of Soluble Trimeric gp140 Structures as Targets for de Novo Docking of First- and Second-Generation Small-Molecule CD4 Mimics
- Creators
- Francesca Moraca - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United StatesKriti Acharya - Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania 19104, United StatesBruno Melillo - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United StatesAmos B Smith - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United StatesIrwin Chaiken - Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania 19104, United StatesCameron F Abrams - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States
- Publication Details
- Journal of chemical information and modeling, v 56(10), pp 2069-2079
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Chemical and Biological Engineering
- Web of Science ID
- WOS:000386315000018
- Scopus ID
- 2-s2.0-84992708800
- Other Identifier
- 991014970023704721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Multidisciplinary
- Computer Science, Information Systems
- Computer Science, Interdisciplinary Applications