Next Article in Journal
Techno-Economic Feasibility of Wastewater Heat Recovery for A Large Hospital in Toronto, Canada
Previous Article in Journal
www.3d-qsar.com: A Portal to Build 3-D QSAR Models
Open AccessAbstract

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.
Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 2019.
Proceedings 2019, 22(1), 77; https://doi.org/10.3390/proceedings2019022077
Published: 15 August 2019
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.
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
MDPI and ACS Style

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. Proceedings 2019, 22, 77. https://doi.org/10.3390/proceedings2019022077

AMA Style

Meuser ME, Murphy MB, Rashad AA, Cocklin S. Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency. Proceedings. 2019; 22(1):77. https://doi.org/10.3390/proceedings2019022077

Chicago/Turabian Style

Meuser, Megan E.; Murphy, Michael B.; Rashad, Adel A.; Cocklin, Simon. 2019. "Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency" Proceedings 22, no. 1: 77. https://doi.org/10.3390/proceedings2019022077

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop