Journal article
Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small‐Molecule CD4 Mimetics and HIV‐1 gp120
ChemMedChem, v 13(6), pp 627-633
20 Mar 2018
PMID: 29337418
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The small‐molecule CD4 mimetics (smCD4mcs) are a class of highly potent HIV‐1 entry inhibitors characterized by a unique structure–activity relationship (SAR). They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water‐filled cavity at the CD4 binding site on the gp120 surface, the so‐called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all led to loss of activity, despite the fact that they are predicted by standard empirical computational approaches to bind equally well, making it difficult to further optimize this region of the compounds to increase binding to gp120. In this study we used quantum mechanical methods to understand the roots of the interactions between region 1 and the F43 cavity. We clearly demonstrate the presence of halogen bond/σ‐hole and dispersion interactions between region 1 and the F43 cavity residues F376–N377, which are not captured by standard molecular mechanics approaches and the role played by the smCD4mc in the F43 cavity desolvation. These findings rationalize why the halogenated region 1 has proven so difficult to move beyond in smCD4mc optimization, in agreement with experimental evidence.
Cavity filling: Desolvation and σ‐hole/dispersion interactions are the driving forces between the small‐molecule CD4 mimetics halogenated phenyl motif, called region 1, and residues F376–N377 in the HIV‐1 gp120 envelope protein. In this study, we demonstrate that only quantum‐mechanics‐based methods can capture those non‐standard effects, opening a new perspective in the rational optimization of region 1 to improve binding affinity.
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Details
- Title
- Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small‐Molecule CD4 Mimetics and HIV‐1 gp120
- Creators
- Francesca Moraca - Schrödinger IncDavid Rinaldo - Schrödinger GmbHAmos B Smith - University of PennsylvaniaCameron F Abrams - Drexel University
- Publication Details
- ChemMedChem, v 13(6), pp 627-633
- Publisher
- Wiley
- Number of pages
- 7
- Grant note
- National Institutes of Health (P01 GM056550)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000428380000020
- Scopus ID
- 2-s2.0-85041548386
- Other Identifier
- 991014969750504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Pharmacology & Pharmacy