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Molecules 2018, 23(8), 1940; https://doi.org/10.3390/molecules23081940

Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

1
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, PA 19102, USA
2
GE Healthcare Life Sciences, 100 Results Way, Marlborough, MA 01752, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Mahesh Narayan
Received: 9 July 2018 / Revised: 27 July 2018 / Accepted: 1 August 2018 / Published: 3 August 2018
(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)
Full-Text   |   PDF [4352 KB, uploaded 3 August 2018]   |  

Abstract

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (kd) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors. View Full-Text
Keywords: bioisosteres; HIV-1 Env; antiviral; surface plasmon resonance; computer-aided drug design bioisosteres; HIV-1 Env; antiviral; surface plasmon resonance; computer-aided drug design
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Meuser, M.E.; Murphy, M.B.; Rashad, A.A.; Cocklin, S. Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency. Molecules 2018, 23, 1940.

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