Correlation analysis of Baker's studies on enzyme inhibition. 1. Guanine deaminase, xanthine oxidase, dihydrofolate reductase, and complement.

Five correlation equations are presented which relate inhibitory activity of 578 inhibitors of guanine deaminase, xanthine oxidase, dihydrofolate reductase, and complement to their chemical structures. The use of correlation analysis in enzyme studies for drug development is discussed. The importance of indicator variables in such studies is emphasized.

Quantitative structure-activity relationship of chymotrypsin-ligand interactions.

Quantitative structure-activity relationships (QSAR) have been formulated for the interactions of a variety of ligands with chymotrypsin. The parameters Km, k2, k3, kcat, and Ki are found to be strongly dependent on molar refractivity as well as steric and electronic character of the substituents in structures of the type R2CH(COOR3)NHCOR1 where R may be H. A model for binding of D and L esters is presented which gives a consistent view of the binding step, acylation, and deacylation. The model suggests new avenue for exploration.

Partition coefficients and the structure-activity relationship of the anesthetic gases.

Partition coefficients of 32 gaseous anesthetics in the octanol-water system have been determined. It is shown that relative anesthetic potency depends on hydrophobicity of the anesthetic (as defined by log P) and on a polar factor. The presence of a polar hydrogen in the anesthetic greatly increases potency. A quantitative structure-activity relationship is formulated based on these two factors.

Calculation of hydrophobic constant (log P) from pi and f constants.

The highest level of confidence can be placed in calculated log P values when (1) the log P of a parent solute is known, (2) pi constants for the required substituent(s) are available, and (3) the substituents either do not have an effect on groups already present in the parent or else this effect has been previously determined. In some instances there are no values available for any related structures which could serve as a parent; then, rather than substitute groups for hydrogen, it is easier to begin "from scratch", as suggested by Nys and Rekker, and assemble the structure from fragments, each of which has been assigned a hydrophobic value. In the present paper some new log P values for the lower alkanes and the inert gases are analyzed with the view of separating hydrophobic effects according to volume (including branching and flexibility) and polarity. Modified fragment values appear to enable reliable calculations to be made for a wider range of structures than was possible with the originally proposed constants.

Formulation of de novo substituent constants in correlation analysis: inhibition of dihydrofolate reductase by 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines.

A correlation equation based solely on de novo constants was formulated for 105 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines acting as inhibitors of dihydrofolate reductase. An equation with seven indicator variables gives a correlation with a correlation coefficient of 0.903 and a standard deviation of 0.229. The technique used is a modification of the Free-Wilson approach. The results indicate that correlation equations with fewer parameters than the theoretical required to account for all molecular changes may often be encountered. It is also shown that cross-product terms can be used to establish the significance of cooperative substituent effects.

Relationships between octanol-water partition data, chromatographic indices and their dependence on pH in a set of beta-adrenoceptor blocking agents.

A thorough investigation on the dependence of octanol/water distribution coefficients (log D) of basic and amphiprotic beta-blocker drugs on pH and pKa values has been carried out. An attempt is made to clarify the factors which govern the chromatographic parameters (log k') in reversed-phase high performance liquid chromatography (RPLC) in terms of chemical structure and of distribution coefficients. The correlations between log D and log k' of different compounds show that the bulkiness and the branching of nitrogen substituent are controlling factors in RPLC measurements. Finally, an ion pair chromatographic system is considered for the prediction of octanol/water partition coefficients.

Synthesis and muscarinic receptor binding profiles of antagonist benzotriazole derivatives.

A series of benzotriazole derivatives were synthesized and tested in order to determine their activities for muscarinic receptor subtypes (M1, M2 and M3). Binding affinities were measured as KI values by competition against [3H]-N-methylscopolamine in rat cortex, atria and ileum. Pharmacological in vitro tests were performed on isolated tissue preparations (rabbit vas deferens, guinea pig atria and ileum); the compounds showed antimuscarinic activity. The synthesized ligands were characterized by moderate activity; however, some of them displayed interesting selectivity profiles (M2/M1 and M2/M3); particularly, the selectivity exhibited by the benzotriazole derivative 14b was quite similar to that observed for AF-DX 116, a typical M2 specific antagonist.

Synthesis and neurokinin antagonist activity of 2-benzylidene- and 2-benzyl-3-benzylamino quinuclidines.

Molecular modeling studies based on the potent NK-1 antagonist CP-96,345 led us to the identification of some 2-benzylidene- and 2-benzyl-3-benzylaminoquinuclidine derivatives as potential antagonists at the NK receptor subtypes. The synthesized compounds, whose Z/E isomerism has been defined by X-ray analysis, show only moderate potency on the three neurokinin receptors. The possible reasons of the low potency exhibited by the tested compounds are discussed.

The structure-activity relationship of 9-(X-phenyl)guanine inhibitors of xanthine oxidase.

A correlation analysis of the structure-activity relationship in the 9-(X-phenyl)guanine inhibitors of xanthine oxidase has been made. The following equation (see article) has been formulated for 30 derivatives having substituents in the 2-, 3- and 4-positions of the 9-phenyl moiety. C in this expression is the molar concentration of inhibitor causing 50% inhibition of xanthine oxidase. MR-3,4 is the combined molecular refractivity of substituents in the 3- and 4-positions. Molar refractivity is a measure of the polarizability of the substituents; it is assumed in the present instance to be a measure of the dispersion forces between the substituent and the enzyme. The positive coefficient with this term roughly indicates that the greater the number of electrons and the greater their polarizability in the substituent, the more inhibitory are the substituents. Es-2 and Es-4 are Taft steric parameters for functions in the ortho and para positions. The positive coefficients with these two terms indicate that bulky groups in the 2- and 4-positions do not make good inhibitors. This is a proximity effect and is related to the enzymic region near the ortho and para positions. No sigma term occurs in this equation which indicates the lack of importance of the electronic effect of substituents on the phenyl ring as it pertains to inhibitory power. Since the hydrophobic parameter pi was not found to be important, it is assumed that these inhibitors are not binding to hydrophobic space in or on the enzyme; rather, they are interacting with polar space. The implications of this equation for the design of better inhibitors are discussed.

A reanalysis of the structure-activity relationships of sulfonamide derivatives.

A reanalysis of correspondence between electronic distribution of sulfonamides and their antibacterial activity is proposed. Correlation equations show that the rate limiting steps for sulfonamide action on E. coli cell-free system and whole cell system have similar dependence on the negative logarithm of the ionization constant. The existence of a "bilinear relationship" demonstrates that the whole class of compounds has a single mechanism of action and that permeability factors are unimportant in both biological processes.

QSAR of the inhibition of glyoxalase by S-substituted glutathiones.

A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of glyoxalase I from yeast by 37 S-substituted glutathiones: log 1/C = 1.23 pi' + 1.20 MR4 - 0.67 I1 - 0.14 pi'2 + 1.85 C in this expression is the molar concentration of inhibitor producing 50% inhibition, pi' is the usual hydrophobic parameter modified for certain substituents, MR4 is the molar refractivity of certain p-phenyl substituents, and I1 is an indicator variable for those congeners with an acetylated alpha-amino group. This equation should be of help in the design of more effective inhibitors which may be of value in cancer chemotherapy.

["De novo substituent constants" in the study of quantitative structure-activity relationship]. / "De novo substituent constants" nello studio delle correlazioni quantitative struttura chimica-attività biologica

The basic features of the Free-Wilson method for assigning additivity constants to structural features of related compounds is described. The method is presented in considerable operational detail with special emphasis on its development. An original example is discussed. Showing that the substituent constants can be related to more fundamental physico-chemical substituent parameters such as the hydrophobic constants pi.

[Correlative analysis in the study of enzyme-ligand interactions]. / L'analisi correlativa nello studio delle interazioni enzima-leganti.

A comprehensive study on enzyme ligand interactions by QSAR techniques is discussed. Thirteen correlation equations are presented which relate activity of 1086 ligands of isolated chloroplasts, chymotrypsin, dihydrofolate reductase, xanthine oxidase and guanine deaminase to their chemical structures. Two kinds of space within and on the surface of an enzyme are defined by means of pi and MR constants. Emphasis is put on the use of indicator variables as a means of rationalizing special enzyme-ligand interactions. The use of such studies for drug development is discussed.

Structure-activity correlations for antibacterial 1,5-benzodiazepine derivatives on gram-positive cells.

The antibacterial activity of a set of 1,5-benzodiazepine derivatives against Staph, aureus and Strep, pyogenes has been correlated with structural features of the compounds examined. It is shown by means of substituent constants and regression analysis that the lipophilic character of the molecule is the most important factor in determining its activity. Electronic and steric effects appear to be quite important.

[Retrospective analysis of drug projection using correlative technics]. / Dall'analisi retrospettiva alla progettazione di un farmaco mediante l'applicazione di tecniche correlative

The problem of choosing substituents to allow correct correlative analysis according to the "Hausch Approach" is discussed. The problem of colinearity among parameters is considered in a case study on 296 anilides which inhibit the Hill reaction. The difficulty in of determining whether, pi or MR is the important variable in changes in activity is shown. "Cluster analysis" is discussed and proposed as a rational method for the selection of substituents to be introduced into biologically active structure in order to explore the scope of each defined physico-chemical parameter. An example of the use of this method conerning auxin activity of 1- and 2-benzotriazole derivatives is given.

[Correlative analysis of chemical structure - biological activity using Hansch's method: principles and development of the method]. / Analisi correlativa struttura chimica-attivita biologica secondo Hansch: Principi ed evoluzione

The basic principles and developments on which the Hansch multiple parameter approach depends are described. A correlation analysis on the antibacterial activity of 2-Y-4-(X-phenyl)-3H-1,5-benzodiazepines is discussed. The use of indicator varioables is shown to greatly increase one's ability to formulate quantitative structure-activity relationships. This approach allows one to carry out objective studies of massive amounts of chemical and biological data.