Title:Design-Based Peptidomimetic Ligand Discovery to Target HIV TAR RNA Using Comparative Analysis of Different Docking Methods
VOLUME: 14 ISSUE: 6
Author(s):Junjie Fu, Amy Xia, Yao Dai and Xin Qi*
Affiliation:Department of Medicinal Chemistry and Department of Radiation Oncology, University of Florida, Gainesville, FL, 32610, United States.
Keywords:Comparative analysis, computational docking, HIV, TAR RNA, Tat, RNA-ligand interaction.
Abstract:Discovering molecules capable of binding to HIV trans-activation responsive
region (TAR) RNA thereby disrupting its interaction with Tat protein is
an attractive strategy for developing novel antiviral drugs. Computational docking
is considered as a useful tool for predicting binding affinity and conducting virtual
screening. Although great progress in predicting protein-ligand interactions has
been achieved in the past few decades, modeling RNA-ligand interactions is still
largely unexplored due to the highly flexible nature of RNA. In this work, we performed
molecular docking study with HIV TAR RNA using previously identified
cyclic peptide L22 and its analogues with varying affinities toward HIV-1 TAR
RNA. Furthermore, sarcosine scan was conducted to generate derivatives of
CGP64222, a peptide-peptoid hybrid with inhibitory activity on Tat/TAR RNA interaction. Each
compound was docked using CDOCKER, Surflex-Dock and FlexiDock to compare the effectiveness
of each method. It was found that FlexiDock energy values correlated well with the experimental Kd
values and could be used to predict the affinity of the ligands toward HIV-1 TAR RNA with a superior
accuracy. Our results based on comparative analysis of different docking methods in RNA-ligand
modeling will facilitate the structure-based discovery of HIV TAR RNA ligands for antiviral therapy.
