Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study (original) (raw)
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Structure Based Design of Inhibitors of Aspartic Protease of HIV-1
Letters in Drug Design & Discovery, 2005
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-ψ[CH 2 -(r/s)CHOH]-Phe-cores. The IC 50 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.
European Journal of Biochemistry, 2004
The crystal structure of the complex between human immunodeficiency virus type 1 (HIV-1) protease and a peptidomimetic inhibitor of ethyleneamine type has been refined to R factor of 0.178 with diffraction limit 2.5 Å . The peptidomimetic inhibitor Boc-Phe-Y[CH 2 CH 2 NH]-Phe-Glu-Phe-NH 2 (denoted here as OE) contains the ethyleneamine replacement of the scissile peptide bond. The inhibitor lacks the hydroxyl group which is believed to mimic tetrahedral transition state of proteolytic reaction and thus is suspected to be necessary for good properties of peptidomimetic HIV-1 protease inhibitors. Despite the missing hydroxyl group the inhibition constant of OE is 1.53 nM and it remains in the nanomolar range also towards several available mutants of HIV-1 protease. The inhibitor was found in the active site of protease in an extended
Journal of Medicinal Chemistry, 1994
The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-lOl/HIV-l protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'-P2' amide bond. It is a competitive inhibitor with a n apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 %, resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (=El l F,,l-lFclE(F,I), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as a n isosteric replacement for the P1'-P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model. ~~ ~ +The refined coordinates for the complex have been deposited in * Department of Medicinal Chemistry. the Protein Data Bank under the file name 2HOS.
Two-step binding mechanism for HIV protease inhibitors
Biochemistry, 1992
Rate constants for binding of five inhibitors of human immunodeficiency virus (HIV) protease were determined by stopped-flow spectrofluorometry. The two isomers of quinoline-2-carbonyl-Asn-PheW [ CH(OH)CHzN]Pro-0-t-Bu (R diastereomer = 1R; S diastereomer = 1s) quenched the protein fluorescence of HIV protease and thus provided a spectrofluorometric method to determine their binding rate constants. The dissociation rate constants for acetyl-Thr-Ile-Leu\k(CHzNH)Leu-Gln-Arg-NHz (2), (carbobenzyloxy)-P~~*[CH(OH)CHZN]P~O-O-~-BU (3), and pepstatin were determined by trapping free enzyme with 1R as 2,3, and pepstatin dissociated from the respective enzyme-inhibitor complex. Association rate constants of lR, 2, and pepstatin were calculated from the time-dependent inhibition of protease-catalyzed hydrolysis of the fluorescent substrate (2-aminobenzoyl)-Thr-Ile-Nle-Phe(NO~)-Gln-Arg-NH~ (4). The kinetic data for binding of 1s to the protease fit a two-step mechanism. Kd values for these inhibitors were calculated from the rate constants for binding and were similar to the respective steady-state Ki values. Human immunodeficiency virus (HIV) * protease is a 22-kDa dimer of two identical 11-kDa subunits (Meek et al., 1989). The protease maturation from the gag-pol polyproteingeneproduct is autocatalytic (Deboucket al., 1987). Since the protease is required for maturation of infectious HIV particles (Kohl et al., 1988; Peng et al., 1989; Gottlinger et al., 1989), it is a potential target for chemotherapeutic treatment of AIDS. Numerous peptide-based inhibitors and nonpeptide inhibitors have been synthesized [recently reviewed by Huff (1991) and Norbeck and Kempf (1991)l. Some of these compounds inhibit maturation of viral particles in vitro
Bioorganic & Medicinal Chemistry, 1995
A detailed structure-activity relationship of Ca-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (ICso: 0.3 riM; ECso: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.
Proceedings of the National Academy of Sciences, 2006
HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct mechanism can provide important inputs. We present here the three-dimensional structure of a bi-product complex between HIV-1 protease and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 Å resolution, shows the occurrence of the cleavage reaction in the crystal, with the product peptides still held in the enzyme active site. The separation between the scissile carbon and nitrogen atoms is 2.67 Å, which is shorter than a normal van der Waal separation, but it is much longer than a peptide bond length. The substrate is thus in a stage just past the G'Z intermediate described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res 34:790-797]. Because the products are generated in situ, the structure, by extrapolation, can give insight into the mechanism of the cleavage reaction. Both oxygens of the generated carboxyl group form hydrogen bonds with atoms at the catalytic center: one to the OD2 atom of a catalytic aspartate and the other to the scissile nitrogen atom. The latter hydrogen bond may have mediated protonation of scissile nitrogen, triggering peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates in the complex are 2.30 Å apart, indicating a low-barrier hydrogen bond between them at this stage of the reaction, an observation not included in Northrop's proposal. This structure forms a template for designing mechanism-based inhibitors.