Abstract

The Computational Core provides expertise at several stages of the overall Program workflow aimed at the generation of new and improved inhibitors of the HIV-1 Env machine. This expertise includes pharmacophore- based screening of external molecule databases to generate new lead molecules of interest, as well as consultation and simulation-based evaluation of new congeners derived from the extant set of authentic inhibitors already successfully generated by the Program. In each of these cases, we aim both to support the generation of new molecules with superior activity, especially in terms of breadth across HIV-1 strains, and to rationalize with 3D all-atom models the mechanisms by which our inhibitors interact with the HIV-1 envelope glycoprotein complex (Env) in its various conformational states. The Computational Core employs the latest and most reliable computational drug design software as well as custom algorithms for target preparation and conformational sampling based on all-atom molecular dynamics simulations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM056550-22
Application #
9561490
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
2023-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Drexel University
Department
Type
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19102

  Publications

Castillo-Menendez, Luis R; Witt, Kristen; Espy, Nicole et al. (2018) Comparison of Uncleaved and Mature Human Immunodeficiency Virus Membrane Envelope Glycoprotein Trimers. J Virol 92:
Rashad, Adel A; Song, Li-Rui; Holmes, Andrew P et al. (2018) Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus-Cell Interface. J Med Chem 61:5020-5033
Moraca, Francesca; Rinaldo, David; Smith 3rd, Amos B et al. (2018) 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 13:627-633
Castillo-Menendez, Luis R; Nguyen, Hanh T; Sodroski, Joseph (2018) Conformational Differences Between Functional Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J Virol :
Madani, Navid; Princiotto, Amy M; Mach, Linh et al. (2018) A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat Commun 9:2363
Kisalu, Neville K; Idris, Azza H; Weidle, Connor et al. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat Med 24:408-416
Parajuli, Bibek; Acharya, Kriti; Bach, Harry C et al. (2018) Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus. Biochem J 475:931-957
Ma, Xiaochu; Lu, Maolin; Gorman, Jason et al. (2018) HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations. Elife 7:
Johnson, Jacklyn; Zhai, Yinjie; Salimi, Hamid et al. (2017) Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States. J Virol 91:
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:

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