Discovery of novel triazole-based opioid receptor antagonists.

We report the computer-aided design, chemical synthesis, and biological evaluation of a novel family of delta opioid receptor (DOR) antagonists containing a 1,2,4-triazole core structure that are structurally distinct from other known opioid receptor active ligands. Among those delta antagonists sharing this core structure, 8 exhibited strong binding affinity (K(i) = 50 nM) for the DOR and appreciable selectivity for delta over mu and kappa opioid receptors (delta/mu = 80; delta/kappa > 200).

Computational studies of the resistance patterns of mutant HIV-1 aspartic proteases towards ABT-538 (ritonavir) and design of new derivatives.

Kinetic characterization and cross resistance pattern studies of HIV-1 aspartic protase (PR) inhibitors have shown that some mutations cause considerable reduction in inhibition efficiency. We have performed a computational study of the binding of ABT-538 (ritonavir) with wild type (wt) PR and 12 model mutant structures (R8Q, V321, M461, V82A, V82F, V821, I84V, M46I/V82F, M46I/I84V, V32I/I84V, V82F/I84V and V32I/K45I/F53L/A71V/I84V/L89M (6X)) for which inhibition data are available. Our computational studies indicate a significant correlation between computed complexation energies of ABT-538 with the modeled mutant enzyme structures and the corresponding experimental inhibition constants. By evaluating non-bonding interaction energies between the inhibitor and the mutant enzymes, we have carried out a mechanistic analysis to ascertain the reasons underlying the decrease in binding affinities. This analysis indicated that several residues in addition to the mutated residues contribute to the loss of binding. Taking these considerations into account, a number of new derivatives of ABT-538 were designed, so as to increase van der Waal's and hydrogen bonding interactions with selected mutants. A significant improvement in calculated complexation energies towards both mutant and wt PR structures was obtained for several of the redesigned analogues.

Three-dimensional quantitative structure-activity relationship analysis of ligand binding to human sequence antidigoxin monoclonal antibodies using comparative molecular field analysis.

The present study indicates that the newly generated human sequence antidigoxin monoclonal antibody (mAb), 1B3, binds digoxin with a different fine specificity binding than our previously obtained human sequence monoclonal antibodies (mAbs) (Ball, W. J.; et al. J. Immunol. 1999, 163, 2291-2298). Uniquely, 1B3 has a higher affinity for digitoxin than digoxin, the immunizing hapten, and a strong requirement for at least one sugar residue linked to the aglycone (-genin). By means of comparative molecular field analysis (CoMFA), the results of competition binding studies for 56 cardiotonic and hormonal steroids were employed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models for ligand binding to 1B3 and to three additional human sequence mAbs, as well as the murine antidigoxin mAb 40-50 (Mudgett-Hunter, M.; et al. Mol. Immunol. 1985, 22, 447-488). All five 3D-QSAR models yielded cross-validated q(2) values greater than 0.5, which indicates that they have significant predictive ability. The CoMFA StDevCoeff contour plots, as well as the competition results, indicate that 1B3 binds ligands in a manner distinct from the other four mAbs. The CoMFA contour plots for 40-50 were also compared with the known X-ray crystallographic structure of the 40-50-ouabain complex (Jeffrey, P. D.; et al. J. Mol. Biol. 1995, 248, 344-360) in order to identify correlations between residues in the mAb binding site and specific contour plot regions. These 3D-QSAR models and their respective contour plots should be useful tools to further understand the molecular nature of antibody-antigen interactions and to aid in the redesign or enhancement of therapeutic antibodies.

Computational studies on tetrahydropyrimidine-2-one HIV-1 protease inhibitors: improving three-dimensional quantitative structure-activity relationship comparative molecular field analysis models by inclusion of calculated inhibitor- and receptor-based properties.

A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar buried surface areas (BSAs) with the observed values of the binding affinity (pK(I)). Various combinations of these specific inhibitor- and receptor-based properties were also evaluated as additional descriptors to three-dimensional quantitative structure-activity relationship (3D-QSAR) models constructed using comparative molecular field analysis (CoMFA). Linear regression of the observed pK(I) values with E(compl), E(solv)[I], and the BSAs yielded a strong correlation in terms of both self-consistency (r(2) approximately equal to 0.90) and internal predictive ability (r(cv)(2) > 0.50). The 3D-QSAR models obtained from CoMFA using standard partial least-squares (PLS) analysis also yielded a strong correlation between the CoMFA fields and the experimental pK(i) (r(2) = 0.96; r(cv)(2) = 0.58). Various "enhanced" 3D-QSAR models were constructed in which different combinations of the E(compl), E(solv)[I], and BSAs were added as additional descriptors to the default steric-electrostatic CoMFA fields. Inclusion of E(solv)[I] in particular yielded significant improvement in the predictive ability (r(cv)(2) approximately equal to 0.80) of the resultant 3D-QSAR model.