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Biomedical subjects

C Hansch

Publications and source records attributed to C Hansch.

At least 145 records · Page 8Linked to original sources
PubMed1976

On the structure of medicinal chemistry.

The great advances in biochemistry and molecular biology, the development of physical organic chemistry, and the availability of large computers are creating opportunities for restructuring medicinal chemistry. The enormous volume of scientific results relevant to medicinal chemistry which appear with each new round of the journals forces us to make greater efforts to bring the information together in more meaningful patterns. The QSAR paradigm redirects our thinking about structuring medicinal chemistry.

Chemical Phenomena↗
PubMed1976

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.

Aminohydrolases↗
PubMed1976

Correlation analysis of Baker's studies on enzyme inhibition. 2. Chymotrypsin, trypsin, thymidine phosphorylase, uridine phosphorylase, thymidylate synthetase, cytosine nucleoside deaminase, dihydrofolate reductase, malate dehydrogenase, glutamate dehydrogenase, lactate dehydrogenase, and glyceraldehyde-phosphate dehydrogenase.

The inhibitory activity of 1058 inhibitors of the title enzymes has been formulated in 13 equations correlating chemical structure with inhibitory potency. Two types of regions in enzymes have been defined by means of pi and molar refractivity constants. The use of indicator variables has been extensively developed to suggest special enzyme-ligand interactions. Several examples are given of the use of correlation equations in comparing structural features of different systems.

Animals↗
PubMed1976

Inhibition of dihydrofolate reductase. Structure-activity correlations of quinazolines.

A quantitative structure-activity relationship (QSAR) has been formulated for quinazolines causing 50% inhibition of liver dihydrofolate reductase. The QSAR for the quinazolines is compared with QSAR for triazine and pyrimidine inhibitors. The three QSAR suggest new possibilities for the design of inhibitors of mammalian dihydrofolate reductase.

Binding Sites↗
PubMed1976

Dependence of hydrophobicity of apolar molecules on their molecular volume.

Cavity size is the primary determinant of the partition coefficient (P) of apolar solutes between octanol and water. Although the energy of cavity formation would be expected to be related to cavity area, older methods of area calculation give a poorer correlation with log P than does volume. Apolar solutes clearly fall into two classes based on their log P/volume relationship, the distinction possibly being whether the solute exposes mostly hydrogen atoms or unbonded electrons.

Chemical Phenomena↗
PubMed1975

Selection of a reference partitioning system for drug design work.

Consideration of the structural, polar, and transport properties of water-saturated solvent and solvent-saturated water phases of three general and eight specific binary systems leads to the conclusion that the n-octanol-water system is a very good all-round compromise for use as a reference system for biological partitioning in drug design work.

Alcohols↗
PubMed1975

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.

Chlorobenzenes↗
PubMed1975

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.

Anesthetics↗
PubMed1975

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.

Alkenes↗
PubMed1975

Structure-activity relationship in synthetic fibrinolytics. 2-Phenethynylcyclopropanecarboxylates.

The fibrinolytic activity of nine 2-phenethynylcyclopropanecarboxylates was measured in the hanging clot test. The structure-activity relationship is given by log 1/C equals 0.54 log P + 2.01 where P is the octanol-water partition coefficient of the carboxylate ion pair and C is the molar concentration of the drug. The equation obtained for the cyclopropanecarboxylates is compared with similar equations for benzoates, salicylates, and N-phenylanthranilates.

Alkynes↗
PubMed1975

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.

Binding Sites↗
PubMed1975

Kinetics and thermodynamics of the slow hydrophobic deactivation of alpha-chymotrypsin.

A quantitative model for the slow reversible hydrophobic deactivation of alpha-chymotrypsin (alpha-CT) is proposed. Kinetic results are obtained for (1) the situation in which the inhibitor concentration, although remaining constant during the course of a run, can be varied independently of the concentration of nonself-inhibiting substrate, and for (2) the situation in which the self-inhibiting substrate concentration decreases during the course of a run, and independent variation of inhibitor and substrate concentrations is not possible. Excellent quantitative agreement between theory and experiment is obtained for a wide range of conditions using 3-(n-hexanoyl-O-benzoate (with dodecylsulfate as the inhibitor), and 3-(n-decanoyl)-O-benzoate as the self-inhibiting substrate. Activation enthalpies and entropies for the hydrophobic deactivation of alpha-CT by dodecylsulfate and tetradecyltrimethylammonium are determined. For comparison, activation enthalpies and entropies for the alpha-CT hydrolysis of 3-(n-heptanoyl)-O-benzoate are determined; evidence for a thermally induced conformational transition in alpha-CT at 30 degrees C is obtained.

Benzoates↗