Scientific Poster Session IV - Students Research-in-Progress

Students Research in Progress
  Tuesday, October 15, 2024
  08:30 AM–10:00 AM

Abstract

Introduction: Human immunodeficiency virus (HIV) affects 36 million individuals worldwide.¹ It’s a lifelong infection that attacks CD-4 cells and can be fatal.² Current anti-retroviral therapies (ART) are used in combination, attack various points of the virus’s life cycle, but cannot eradicate a latent virus. Latent HIV can be re-activated, making finding a cure a challenge.³ This project aims to cure HIV and transform the current treatment landscape.

Research Question or Hypothesis: To propose the discovery and design of selective histone deacetylase 3 (HDAC3) negative allosteric modulators (NAMs) to activate latent HIV that can subsequently be neutralized by established ART. We hypothesize that targeting the less explored and conserved co-repressor allosteric site can design HDAC selective NAMs.

Study Design: Experimental

Methods: Schrödinger, a software, was utilized to screen our chemical library to identify “hit” molecule(s) predicted to bind to an allosteric site of HDAC3. Glide scores ranked binding abilities and identified possible hits. To improve potency and selectivity, computer-guided optimization of molecules with IC₅₀ <10µM was conducted and created a drug library of analogs. HDAC3 fluorogenic screening assay assessed the inhibitory activity of analogs and was tested at 6 concentrations. SpectraMax detected fluorescence emission, a dose-response curve was generated, and GraphPad prism calculated IC₅₀.

Results: Schrödinger preliminary results yielded a hit molecule, 1051, with an IC₅₀ of 5.11µM. The optimized analog, RR-125-39, computed an XP score of -8.214 kcal/mol and SP of -7.873 kcal/mol. Only 38% inhibition was found at 20uM inhibition. 1051 and RR-125-1 portrayed 86% and 98% inhibition respectively. 1051 had a XP of -8.177 kcal/mol and SP of -9.134 kcal/mol; RR-125-11 score of -2.097 kcal/mol, XP, and SP of -2.896 kcal/mol.

Conclusion: Two HDAC3 NAMs were identified and indicate the need to further explore structure activity relationship of hit molecules. This project hopes to design lead molecules with improved pharmacodynamic and pharmacokinetic properties and eventually develop a drug.

Presenting Author

Shilpa Francis BS
Concordia University Wisconsin

Authors

Christopher Cunningham PhD
Concordia University Wisconsin

Ashley Mayer .
Concordia University Wisconsin

Terry E. Reid PhD
Concordia University Wisconsin

Jocelyn Wilson .
Concordia University Wisconsin