Heterobiaryl Human Immunodeficiency Virus Entry Inhibitors

Lü, Rui; Tucker, John; Pickens, Jason C.; Ma, Yao; Zinevitch, Tatiana; Kirichenko, Olga; Konoplev, Vitalii E.; Kuznetsova, Svetlana; Свиридов, С. И.; Brahmachary, Enugurthi; Khasanov, Alisher; Mikel, Charles; Yang, Yang; Liu, Changhui; Wang, Jian; Freel, Stephanie A.; Fisher, Shelly; Sullivan, Alana; Zhou, Ji; Stanfield-Oakley, Sherry; Baker, Brian; Sailstad, Jeff; Greenberg, Michael; Bolognesi, Dani P.; Bray, Brian L.; Koszalka, Barney; Jeffs, Peter W.; Jeffries, Cynthia; Chucholowski, Alexander; Sexton, Connie J.

doi:10.1021/jm900330x

Cited by 35 publications

(14 citation statements)

References 40 publications

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“…The substitutions on the aza‐indole ring have been shown to affect the inhibitory activities of BMS‐488 in quite different ways 82, 83. On the basis of present model we are trying to understand how different substituents on the aza‐indole lead to distinct effects to their activities.…”

Section: Resultsmentioning

confidence: 99%

Understanding the binding mode and function of BMS‐488043 against HIV‐1 viral entry

Quan

2011

Proteins

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A recently discovered small-molecule inhibitor, BMS-488043 (BMS-488), for the invasion of Human immunodeficiency virus Type 1 (HIV-1), shows a high activity against the entry of diversified HIV-1. Docking and molecular dynamic studies have been carried out to understand the binding mode of BMS-488 to gp120 as well as the effect of the small molecule on the conformational change of gp120 induced by CD4 binding. The results indicate that BMS-488 can accommodate in the CD4 binding pocket and interfere the CD4 binding in a noncompetitive mode. The piperazine group of BMS-488 prevents the bridging sheet formation of gp120 induced by the CD4 binding mainly through blocking the rotation of the Trp112 located on the α1 helix of gp120. The bridging sheet formation cannot be blocked for the W112A mutant of gp120 due to the reduced steric hindrance, in agreement with its significant resistance to the BMS inhibitor. The aza-indole ring is likely to interfere the exposure of gp41 by stacking within the β3-β5 and LB loops to disrupt the close packing of Pro212-His66-Phe210. The mode of action of BMS-488 also accommodates many mutagenesis results related to BMS-488 activity.

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Section: Resultsmentioning

confidence: 99%

Understanding the binding mode and function of BMS‐488043 against HIV‐1 viral entry

Quan

2011

Proteins

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“…The inhibition of CD4–gp120 binding or the ensuing signaling cascade has been recognized as a valid strategy to block viral entry. In fact, several small molecular-weight inhibitors that target gp120 have been developed and tested in binding and cell-inhibition assays [27–34], and very recently in humans [36,37]. As of yet, however, the mechanistic character of these inhibitors is only partially known.…”

Section: Hiv-1 Cell-entry Inhibitorsmentioning

confidence: 99%

Thermodynamics-Based Drug Design: Strategies for Inhibiting Protein–Protein Interactions

Schön

Lam

Freire³

2011

Future Med. Chem.

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The inhibition of protein–protein interactions and their ensuing signaling processes play an increasingly important role in modern medicine. Small molecular-weight inhibitors that can be administered orally are the preferred approach but efficient strategies for developing them are not yet generally available. Due to the large size difference between the protein–protein interface and the small molecule, inhibitor interactions are expected to extend to only a small region of the interface. If this is the case, classical competitive inhibition may be hard to achieve. In addition, competitive inhibition wastes binding energy that can be effectively used to inhibit signaling. The best and most energy-efficient approach would be the development of small molecules that bind at the protein–protein interface and inhibit the signaling process without displacing the protein ligand. This approach seems feasible knowing that the binding energy is not evenly distributed within the binding interface but concentrated in discrete hotspots, and that the initiation of signaling may not overlap with those hotspots. We outline a general protein–protein inhibition model that extends from competitive to noncompetitive scenarios and apply it to the development of HIV-1 gp120-CD4 inhibitors. This rigorous model can be easily applied to the analysis of protein–protein inhibition data and used as a tool in the optimization of inhibitor molecules.

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“…The most potent inhibitor (13h) (Figure 1), of the dataset 41 was drawn using SYBYL 8.1 42 software package. Minimization was performed with the Tripos force field using 1000 steps of steepest descent algorithm followed by the 1000 steps of conjugate gradient algorithm.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Binding Mode of the Heterobiaryl gp120 Inhibitor in HIV-1 Entry: A Molecular Docking and Dynamics Simulation Study

Gadhe¹,

Kothandan²,

Cho

2013

Bulletin of the Korean Chemical Society

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Human immunodeficiency virus type-1 (HIV-1) is a causative agent of Acquired immunodeficiency syndrome (AIDS), which has affected a large population of the world. Viral envelope glycoprotein (gp120) is an intrinsic protein for HIV-1 to enter into human host cells. Molecular docking guided molecular dynamics (MD) simulation was performed to explore the interaction mechanism of heterobiaryl derivative with gp120. MD simulation result of inhibitor-gp120 complex demonstrated stability. Our MD simulation results are consistent with most of the previous mutational and modeling studies. Inhibitor has an interaction with the CD4 binding region. Van der Waals interaction between inhibitor and Val255, Thr257, Asn425, Met426 and Trp427 were important. This preliminary MD model could be useful in exploiting heterobiaryl-gp120 interaction in greater detail, and will likely to shed lights for further utilization in the development of more potent inhibitors.

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Heterobiaryl Human Immunodeficiency Virus Entry Inhibitors

Cited by 35 publications

References 40 publications

Understanding the binding mode and function of BMS‐488043 against HIV‐1 viral entry

Understanding the binding mode and function of BMS‐488043 against HIV‐1 viral entry

Thermodynamics-Based Drug Design: Strategies for Inhibiting Protein–Protein Interactions

Characterization of Binding Mode of the Heterobiaryl gp120 Inhibitor in HIV-1 Entry: A Molecular Docking and Dynamics Simulation Study

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