LAUSR

HIV-1 protease (HIVPR) is an important drug target to combat AIDS. This enzyme is an aspartyl protease that is functionally active in its dimeric form. NMR reports have convincingly shown that there exists a pseudo-symmetry at the HIVPR active site, where only one of the two aspartates remains protonated over the pH range of 2.5-7.0. Till date, all HIVPR-targeted drug designing 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 lacked effectiveness with the emergence of drug-resistant protease variants, majorly 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 specific mode of substrate binding involves significant electrostatic interactions, none of the existing drugs/inhibitors could utilize this electrostatic hotspot. 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 way for the promising designs that might be more effective against both wild type and HIVPR resistant variants.