Structure Based Design of Inhibitors of Aspartic Protease of HIV-1

Abstract

The aspartic protease of HIV-1 represents a valid therapeutic target of antiviral agents suitable for the treatment of AIDS. We have designed peptidomimetic inhibitors for this enzyme with a hydroxyethylenediamine core, based on a molecular modeling approach that predicts the effectiveness of the designed compounds in terms of computed enzyme-inhibitor complexation Gibbs free energies. This structurebased molecular design was then combined with a synthetic strategy that couples stereochemical control with full flexibility in the choice of the central core side chains and of the flanking residues. A series of peptidomimetic inhibitors was thus assembled from readily available amino acids and carboxylic acids and -Phe-ω[CH2-(r/s)CHOH]-Phe- cores. The IC50 values for these compounds ranged from 3 nM to 80 μM, allowing a QSAR analysis and identification of factors that determine the inhibition potency of the compounds. Predicted ADME-related properties of the inhibitor candidates span a range of pharmacokinetics profiles, which allows selection of a potent and bioavailable lead compound for further development

<i>In silico</i> Design of Phosphonic Arginine and Hydroxamic Acid Inhibitors of <i>Plasmodium falciparum</i> M17 Leucyl Aminopeptidase with Favorable Pharmacokinetic Profile

“…This Computational approach successfully narrows the filter and accelerates the process to new lead compounds compared with traditional synthesis approach. This was observed for peptide and peptidomimetic inhibitors of HIV-1 [16,17] and hepatitis C (HCV) [15] virus proteases design, for combinatorial design of bicyclic thymidine analogues [22] and complexation structure-based design of thymidine analogues [21,23] inhibitors of Mycobacterium Tuberculosis (MTb) thymidine monophosphate kinase, to provide insight into selectivity of peptidomimetic inhibitors with modified statine core for pf Plasmepsin II over human Cathepsin D [18]. Recently a complete process starting from the complexation QSAR model and its derived 3D-QSAR four features Pharmacophore (PH4) model have successfully served to screen a large Virtual Library of 1.6 million compounds reaching one hundred orally bioavailable pyrrolidine carboxamide inhibitors of MTb enoyl acyl carrier protein reductase (InhA) [24].…”

“…The complexation methodology has been described largely accor-ding to a procedure successfully used to elaborate one descriptor QSAR models of viral, bacterial and protozoal protease-inhibitor complexes and from them to design peptidomimetic, hydroxylnaphthoic, thymidine, triclosan and pyrrolidine carboxamide derivative inhibitors [15,16,17,18,19,20,21,22,23,24].…”

Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing –PheΨPro– core and displaying favourable ADME-related properties

“…In this work we approximate the exact values of standard Gibbs free energies for larger systems such as enzyme:inhibitor complexes by the expression [9,11,13]: …”

“…Our laboratories have developed an integrated method for the design and synthesis of peptidomimetic C 2 -symmetric inhibitors based on a modular assembly of appropriate flanking residues onto non-hydrolysable mono and dihydroxyethylenediamine cores [8][9][10][11][12][13]. The synthetic route used by our group is based on available starting materials and allows full flexibility and stereoselective synthesis of the central hydroxylated ethylenediamine core with the possibility to vary independently the P 1 and P 1 0 residues in the central unit as well as the number and type of P n , P n 0 residues flanking the central core on either side [7,[14][15][16].…”

“…The synthetic route used by our group is based on available starting materials and allows full flexibility and stereoselective synthesis of the central hydroxylated ethylenediamine core with the possibility to vary independently the P 1 and P 1 0 residues in the central unit as well as the number and type of P n , P n 0 residues flanking the central core on either side [7,[14][15][16]. Using this methodology, we have prepared a series of peptidomimetic inhibitors containing 4, 5 or 6 residues and ranging from C 2 -symmetrical to non-symmetrical ones composed of building blocks of natural and non-natural amino acids and carboxylic acids [8][9][10][11][12][13].…”