Electrostatics Plays a Crucial Role in HIV-1 Protease Substrate Binding, Drugs Fail to Take Advantage

Abstract

HIV-1 protease (HIVPR) is an important drug target for combating AIDS. This enzyme is an aspartyl protease that is functionally active in its dimeric form. Nuclear magnetic resonance reports have convincingly shown that a pseudosymmetry exists at the HIVPR active site, where only one of the two aspartates remains protonated over the pH range of 2.5–7.0. To date, all HIVPR-targeted drug design strategies focused on maximizing the size–shape complementarity and van der Waals interactions of the small molecule drugs with the deprotonated, symmetric active site envelope of crystallized HIVPR. However, these strategies were ineffective with the emergence of drug resistant protease variants, primarily due to the steric clashes at the active site. In this study, we traced a specificity in the substrate binding motif that emerges primarily from the asymmetrical electrostatic potential present in the protease active site due to the uneven protonation. Our detailed results from atomistic molecular dynamics simulations show that while such a specific mode of substrate binding involves significant electrostatic interactions, none of the existing drugs or inhibitors could utilize this electrostatic hot spot. As the electrostatic is long-range interaction, it can provide sufficient binding strength without the necessity of increasing the bulkiness of the inhibitors. We propose that introducing the electrostatic component along with optimal fitting at the binding pocket could pave the way for promising designs that might be more effective against both wild type and HIVPR resistant variants.

Electrostatic features for the Receptor binding domain of SARS-COV-2 wildtype and its variants. Compass to the severity of the future variants with the charge-rule

“…12 It was also been shown that efficient drugs binding to HIV require specific electrostatic features. 13 Moreover, pH is well known to trigger several key biological events for viruses. For instance, a drop in pH is often used to allow the host penetration.…”

Mechanism of darunavir binding to monomeric HIV-1 protease: a step forward in the rational design of dimerization inhibitors

“…Each monomer is made up of 99 amino acids and the active site located at the dimer interface is constituted by two catalytic aspartate residues, one from each monomer. [2][3][4] Currently, there are ten FDA approved drugs that act against HIVPR and all these drugs bind to the dimeric form of the enzyme. These drugs compete with the substrates for the binding to the active site of HIVPR dimer.…”

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

“…Electrostatic interaction energies are usually the largest components of the interaction energy, followed by energies of exchange-repulsion, induction, and dispersion. Even if electrostatic interactions are not always the strongest one, due to being long-range and often directional, they make a dominant contribution to the relative orientation of the enzyme and substrate and therefore to molecular recognition and substrate specificity [30][31][32][33][34]. Electrostatic energies have also been shown to be a more reliable indicator of relative biding strength than more accurate total energies when dealing with questionable geometries [35].…”