Abstract
While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.
Highlights
In recent years, HIV-1 CA has emerged as a major drug target for antiviral therapeutic development [1,2,3]
While drug resistance mutations are often attributed to the loss of direct or solventmediated protein–ligand interactions in the drug-mutant complex [20], in this study we demonstrate that the molecular basis for the M66I resistance mutation of GS-6207 is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein
The experimental data show that the M66I mutation leads to an >84,000-fold reduction in the activity of GS-6207, a picomolar HIV-1 capsid-targeting antiviral, while the same mutation leads to only a 68-fold reduction in the activity of the newly designed antiviral ZW-1261 and a 83-fold loss in the activity of PF74
Summary
HIV-1 CA has emerged as a major drug target for antiviral therapeutic development [1,2,3]. Small molecule agents with different chemotypes have been developed in recent years to disrupt the CA biological functions in the virus replication cycle [9,10,11,12]. Recent studies have identified several amino acid mutations in the CA binding site that confer drug resistance to GS-6207 [13,14]. M66I causes the greatest reduction in GS-6207 antiviral activity by up to ~84,000-fold compared to WT HIV-1 CA [14]. The same mutation causes a resistance of only 83-fold to PF74 and 68-fold to the PF74 derivative ZW-1261 [5,9,15] (Figure 1 and Table 1).
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