Human immunodeficiency virus (HIV) impacts over one million people in the United States alone. While there are antiretrovirals that effectively manage the disease, resistance to current drugs is emerging. Non-canonical nucleic acid structures, such as G-quadruplexes (GQs), are promising targets for small-molecule drug design against viral replication. HIV-1 replication relies on two mutually exclusive GQs, LTR-III and LTR-IV, which are structurally distinct and inversely regulate viral gene expression. Efforts to target GQs have been limited by a lack of selectivity in known binding compounds as they primarily bind to the tetrad core found in all GQs. Here, the LTR-III and LTR-IV GQs serve as a platform to study how compounds can discriminate between distinct GQ structures for improved drug design based on dynamic and electronic properties.
We first employed polarizable molecular dynamics simulations to study the dynamic and electronic properties of LTR-III. We observed that Ade4:Thy14 and Gua3:Thy14 base pairs formed at the quadruplex:duplex junction, a common target for GQ-binding ligands. Despite not being present in the NMR ensemble, Ade4:Thy14 fits the NOE data and was observed in prior simulations using the AMBER force field. Ade4:Thy14 was more prevalent than Gua3:Thy14 and analysis of the intrinsic electric field and the base dipole moments rationalize the preference for Ade4:Thy14. The conformational free energy associated with Ade4:Thy14 states is lower than that of Gua3:Thy14, but the 2-3 kcal/mol energy barriers between these states suggest that Thy14 may readily interact with both bases, modulating the properties and accessibility of a likely drug binding site. We then used Site Identification by Ligand Competitive Saturation to screen common drug fragments against these states and to determine how this conformational flexibility modulates affinity patterns of drug-like moieties. Our results represent a critical step toward the rational design of selective compounds for LTR-III.

Siena Morlatt

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