Calculation of NH...pi hydrogen bond energies in basic pancreatic trypsin inhibitor.

Ab initio molecular orbital procedures have been employed to investigate associations of the Tyr35 aromatic ring with Gly37 NH and Asn44 NHz in the X-ray crystal structure of basic pancreatic trypsin inhibitor. Formamide and phenol were used to model the key features in the protein. The calculations provide evidence for energetically favorable NH...pi hydrogen bonding.

Structure-activity relationships for drugs binding to the agonist and antagonist states of the primary morphine receptor.

Thirty-three opiate drugs have been considered in an investigation of the geometric and electronic features required for association with the agonist and antagonist states of the principal morphine receptor. Conformational analysis was carried out by means of molecular mechanics, and electronic properties were calculated with an ab initio SCF-MO procedure using FSGO basis sets. Statistical analysis of receptor binding based on a free-energy model reveals several properties of the molecules under study that affect the stability of the drug-receptor complex. The results suggest that the same drug conformation is involved in binding at both the agonist and antagonist states of the receptor. A single set of drug features serves to rationalize association with both receptor states, but differences in binding-site topography are revealed by the relative importance of the various structural features in the regression equations for the two states.

Effect of sodium ion on the affinity of naloxone for the kappa opioid receptor.

Several investigators have observed that sodium ion enhances the binding of naloxone to opioid receptors. This effect has generally been attributed to allosteric modulation of the state of the mu receptor. However, a recent claim has been made that the enhancement does not involve a change in the mu receptor, but instead occurs because naloxone becomes a more kappa-specific drug when sodium ion is present in high concentration. Since the claim was not based on experimental evidence from binding studies involving known high-affinity kappa ligands, we have investigated the competition of naloxone for the kappa site using [3H]U-69593 as the marker for receptor binding. Assays were carried out in the presence and absence of 100 mM NaCl. The results of the study indicate that sodium ion does not increase the affinity of naloxone or U-69593 for the kappa receptor.

Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl]benzamides at the primary morphine receptor.

In this paper, we describe the synthesis of a series of trans-N-[2-(methylamino)cyclohexyl]benzamides possessing morphine-like pharmacological properties. The affinity of the compounds for the agonist and antagonist states of the mu opioid receptor has been established by means of an in vitro binding assay. We have investigated the geometry and electronic structure of the molecules using molecular mechanics and an ab initio SCF-MO procedure with FSGO basis sets. Comparison to naloxone reveals properties of possible importance in receptor association. We have considered both the S,S and R,R isomers in the binding model. Statistical analyses imply that three factors play a significant role in binding: (1) membrane-water partitioning, (2) the capacity of the aromatic ring and amine N-substituent to act as electron acceptors, (3) the conformational energy required to attain the binding configuration.

Structure-activity correlations for a series of antiallergy agents. 2. Geometric and electronic characterization of some oxamic and dioxamic acids.

Hartree-Fock self-consistent field calculations using the ab initio molecular fragment technique have been performed on some phenyloxamic and m-phenylenedioxamic acids, which exhibit markedly different activities in the rat passive cutaneous anaphylaxis (PCA) assay. Attention is focused upon structural features that are most likely to affect the drug-receptor interactions, such as the preferred molecular geometry, the electronic charge distribution, and the nature of the higher occupied (HOMO) and lower unoccupied (LUMO) molecular orbitals. Judging from the regions of high density in HOMOs and LUMOs, the benzene ring would preferably act as an electron acceptor, while the oxamic acid moiety would serve best as an electron donor. Factors affecting the relative PCA activities of oxamic and dioxamic acids are discussed.

Structure-activity correlations for a series of antiallergy agents. 3. Development of a quantitative model.

A nonlinear regression model has been employed to investigate the activity of a series of 51 drugs in the rat passive cutaneous anaphylaxis assay. Although several classes of molecules are represented in the sample, there are certain common structural features that enable detailed geometric and electronic comparisons to be made. Ab initio Hartree-Fock SCF calculations were performed by using the molecular fragment approach to characterize the electronic structure and preferred conformations of the molecules. The statistical results establish the importance of nine structural factors in determining the potency as inhibitors of histamine release. Both the conformation of a drug and its capacity to act effectively as an electron acceptor in charge-transfer interactions are shown to be critical for high activity.

An analysis of binding at the opioid receptor based upon an agonist/antagonist two-state model.

Experimental binding data for a number of opioid agonists and antagonists in homogenate of rat brain membranes at 0 degrees have been analyzed in terms of the two-state Snyder-Pert receptor model. By means of iterative nonlinear regression techniques, it was possible to evaluate the affinity constants characterizing the binding of each drug at the agonist and antagonist states of the receptor. In addition, the role of Na+ in determining the state of the receptor has been described quantitatively. The findings of this study are discussed in terms of the index, fr, which provides a theoretical measure of the fraction of receptors existing in the agonists state. The graph of fr as a function of drug concentration may be reasonably interpreted as an ideal dose-response curve which might be obtained if the drug were introduced directly at the receptor. The implications of the findings with respect to receptor operation are discussed. Although the binding constants have not been found under physiological conditions, the results indicate that the receptor mechanism remains essentially intact in the brain membrane preparation.

Drug affinities for the agonist and antagonist states of the opioid receptor.

Traditional methods of analyzing the binding of opiates do not accurately establish the affinities of the drugs for the agonist and antagonist states of the opioid receptor. The poor results obtained by the Scatchard procedure may be attributed to the presence of extraneous drug binding sites in the brain-homogenate medium. In this study a nonlinear regression technique has been employed to analyze receptor binding in terms of the two-state Snyder-Pert model while simultaneously considering drug association with the aggregate of non-receptor binding sites. Results are reported for naloxone, pentazocine, and dihydromorphine, which respectively represent a pure antagonist, a mixed agonist-antagonist, and a pure agonist. the affinity constants characterizing equilibrium binding at the agonist and antagonist states of the receptor at 37 degrees C are given for each of the three drugs. In addition, a theoretical index, f tau, is defined which provides a measure of the fraction of receptors existing in the agonist state. It is found that the graft of f tau vs log [D] exhibits features similar to the in vivo dose-response curves for the drugs.

Structure-activity correlations for a series of antiallergy agents. Oxanilic, quinaldic, and benzopyran-2-carboxylic acids.

Ab initio Hartree-Fock SCF calculations with the molecular fragment technique have been performed on several drugs which exhibit activity in the rat passive cutaneous anaphylaxis (PCA) assay. Representative molecules of the following types were included in the series: oxanilic acids, 1,4-dihydro-4-oxoquinaldic acids, and 4-oxo-4H-1-benzopyran-2-carboxylic acids. A quantitative relationship has been established between the observed biological activity and an electronic index obtained from the calculations. The correlation is rationalized in terms of charge-transfer stabilization of the drug-receptor complex.