Abstract
The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with “secondary” targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions.
Highlights
3), descriptors, the well-established ligand-based comcomputational approaches centered on
If the advent of saquinavir—the first HIV-1 PR inhibitor—in 1995, symbolized a fundamental step for the treatment of HIV-infected patients, the daily and prolonged use of these agents caused many side-effects, some of which were unbearable. This is due to the capability of a lot of these drugs to interact, with the principal target HIV-1 PR, and with other “secondary” targets involved in metabolic regulation and cell proliferation
We reported a new, reliable, mixed in-silico ligand/structure-based protocol that use on/off-targets, in order to select new possible leads, such as HIV-1 PR
Summary
Retroviral HIV-1 PRotease (HIV-1 PR), called retropepsin, plays an essential role in the process of maturation of non-infectious spherical virions. The substitutions with Asn, Thr,25or Ala lead to an enzyme without any proteoThe mutational analysis of both Asp residues demonstrates their central role in lytic activity [5,9,13,14,15]. These two key residues are planar and interact strictly with subthe catalysis. These residues coordinate a proteolytic activity [5,9,13,14,15] These two key residues are planar and interact strictly with molecule of water to hydrolyze the specific peptide bond, with the formation of an oxysubstrates and inhibitors [16]. Seven peptide bond located between the fourth and fifth residues, starting from the N terminus [23]
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