Molecular Shape Analysis Research Articles

Molecular orbital study of the ring nitrogen basicity of various dihydrofolate reductase inhibitors

AbstractWe present molecular orbital (CNDO/2) calculations on the key fragments of different dihydrofolate reductase inhibitors. Distance geometry analysis, physicochemical parameter dependent QSAR, and molecular shape analysis raised some questions regarding the basicity of the ring nitrogen (N1) in these inhibitors and the effect of the various substituents on the basicity. We show that the ring nitrogen N1 of methotrexate has a considerably higher tendency to be protonated compared to that of folic acid. However, not all 2,4‐diamino inhibitors are equally basic. Even 2‐amino‐4‐hydroxyquinazoline is sufficiently basic to be protonated, but not the 2,4‐diamino‐5‐sulfonyl derivatives. The pyrimidinium ion seems to be highly solvated, since in spite of its high protonation energy it is strongly basic. Triazines were found to be the most basic of all the classes studied.

A QSAR Study of the Ames Mutagenicity of 1‐(X‐Phenyl)‐3,3‐dialkyltriazenes Using Molecular Potential Energy Fields and Molecular Shape Analysis

AbstractA set of 18 1‐(X‐phenyl)‐3,3‐dialkyltriazenes whose mutagenic potencies have been measured were investigated in terms of their potential energy fields. Molecular shape analysis, MSA, was applied to the potential energy field data and a QSAR established. The MSA descriptor, common overlap steric volume between pairs of molecules, found to be a correlate in a previous study [1] is replaced in this study by what physically appears to be the difference in dispersion binding energy between pairs of molecules. A separate investigation of the interrelationship between molecular dielectric representation and corresponding potential energy field based MSA descriptors was carried out. Single molecule MSA descriptors derived from electrostatic energetics are quite dependent on dielectric form, while corresponding pairwise difference MSA features exhibit only a marginal relationship.

ChemInform Abstract: THEORY AND APPLICATION OF MOLECULAR POTENTIAL ENERGY FIELDS IN MOLECULAR SHAPE ANALYSIS: A QUANTITATIVE STRUCTURE‐ACTIVITY RELATIONSHIP STUDY OF 2,4‐DIAMINO‐5‐BENZYLPYRIMIDINES AS DIHYDROFOLATE REDUCTASE INHIBITORS

A general formalism, based upon molecular mechanics pairwise potential functions, has been developed to compute the molecular potential energy fields inherent to a given molecule in a given conformation. Molecular descriptors are derived from the potential energy fields, which can be used in QSAR studies based upon molecular shape analysis. These descriptors have been computed for a set of 2,4-diamino-5-benzylpyrimidines that are dihydrofolate reductase (DHFR) inhibitors. A QSAR is derived in which DHFR inhibition activity can be explained in terms of molecular shape, as represented by differences in molecular potential energy fields between pairs of superimposed molecules, and the sum of the pi constants of substituents on the 3- and 4-position of the benzyl ring. This QSAR is superior to one developed earlier (Hopfinger, A. J. J. Med. Chem. 1981, 24, 818) in which molecular shape is described by common overlap steric volume. Ancillary information defining the active conformation and electrostatic nature of the binding site are realized in the construction of the QSAR.

Intrinsic mutagenicity of polycyclic aromatic hydrocarbons: A quantitative structure activity study based upon molecular shape analysis

The mutagenic potencies of 30 polycyclic aromatic hydrocarbons, (PAHs) were quantitatively related to the physicochemical properties of the parent structures. The goal of the work was to identify how much information regarding overall mutagenicity of PAHs reside in the unmetabolized structures. Quantitative structure activity relationships (QSARs) were established between measured mutagenic potency and two molecular properties: (1) ΔE, the difference in energy between the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), and, (2) molecular shape, as measured by common overlap steric volumes between pairs of PAHs. Mutagenic potency can be predicted with an average error of about ±11% for these 30 PAHs. It appears that the physicochemical properties of a parent PAH dictate much of the mutagenic behavior ultimately realized through metabolic activation. Consequently, QSARs developed for the parent PAHs might serve as reliable empirical guides in ranking mutagenic potency.

ChemInform Abstract: INHIBITION OF DIHYDROFOLATE REDUCTASE: STRUCTURE‐ACTIVITY CORRELATIONS OF 2,4‐DIAMINO‐5‐BENZYLPYRIMIDINES BASED UPON MOLECULAR SHAPE ANALYSIS

A quantitative structure-activity relationship (QSAR) investigation of a set of 23 substituted 2,4-diamino-5-benzylpyrimidines spanning an activity range of 1.8 log (1/C) units was carried out using molecular shape analysis (MSA). C is the molar concentration necessary for 50% inhibition of bovine liver dihydrofolate reductase (DHFR). The active shape of these compounds was deduced by comparing the change in conformational state to the activity of four compounds outside the data base described above. A correlation equation, and analogous in descriptor form to those developed earlier for DHFR inhibition by substituted, 2,4-diaminotriazines and -quinazolines, was constructed. The correlations coefficient, r, was 0.931 and the standard deviation of fit, s, was 0.137. The results suggest that these pyrimidines bind to DHFR with shape features different from both the triazines and quinazolines. It is postulated from the active shape of the pyrimidines that it is preferable to substitute at the meta position of the benzyl ring rather than at the para position.

ChemInform Abstract: INHIBITION OF DIHYDROFOLATE REDUCTASE: STRUCTURE‐ACTIVITY CORRELATIONS OF QUINAZOLINES BASED UPON MOLECULAR SHAPE ANALYSIS

Chemischer InformationsdienstVolume 12, Issue 47 Other Subjects ChemInform Abstract: INHIBITION OF DIHYDROFOLATE REDUCTASE: STRUCTURE-ACTIVITY CORRELATIONS OF QUINAZOLINES BASED UPON MOLECULAR SHAPE ANALYSIS C. BATTERSHELL, C. BATTERSHELLSearch for more papers by this authorD. MALHOTRA, D. MALHOTRASearch for more papers by this authorA. J. HOPFINGER, A. J. HOPFINGERSearch for more papers by this author C. BATTERSHELL, C. BATTERSHELLSearch for more papers by this authorD. MALHOTRA, D. MALHOTRASearch for more papers by this authorA. J. HOPFINGER, A. J. HOPFINGERSearch for more papers by this author First published: November 24, 1981 https://doi.org/10.1002/chin.198147312AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume12, Issue47November 24, 1981 RelatedInformation

Inhibition of dihydrofolate reductase: structure-activity correlations of 2,4-diamino-5-benzylpyrimidines based upon molecular shape analysis.

A quantitative structure-activity relationship (QSAR) investigation of a set of 23 substituted 2,4-diamino-5-benzylpyrimidines spanning an activity range of 1.8 log (1/C) units was carried out using molecular shape analysis (MSA). C is the molar concentration necessary for 50% inhibition of bovine liver dihydrofolate reductase (DHFR). The "active" shape of these compounds was deduced by comparing the change in conformational state to the activity of four compounds outside the data base described above. A correlation equation, and analogous in descriptor form to those developed earlier for DHFR inhibition by substituted, 2,4-diaminotriazines and -quinazolines, was constructed. The correlations coefficient, r, was 0.931 and the standard deviation of fit, s, was 0.137. The results suggest that these pyrimidines bind to DHFR with shape features different from both the triazines and quinazolines. It is postulated from the "active" shape of the pyrimidines that it is preferable to substitute at the meta position of the benzyl ring rather than at the para position.

Inhibition of dihydrofolate reductase: structure-activity correlations of quinazolines based upon molecular shape analysis.

A quantitative structure-activity relationship (QSAR) investigations of a set of 35 substituent-diverse quinazolines spanning an activity range of 4.16 log (1/I50) units was carried out using molecular shape analysis (MSA). I50 is the molar concentration necessary for 50% inhibiton of rat liver dihydrofolate reductase (DHFR). A correlation equation, analogous in descriptor form to those developed for two sets of 2,4-diaminotriazines which are also DHFR inhibitors, was constructed. The correlation coefficient, r, is 0.965, and the standard deviation, s, is 0.360. A second correlation equation was developed to explain the activities of the quinazolines on the basis of their shape similarity to a 2,4-diaminotriazine in its postulated active conformation as determined in a previous study. This correlation equation is again identical in descriptor form with those previously constructed for the triazines and quinazolines; r = 0.945 and s = 0.451 for this correlation equation. The ability to quantitatively explain activity in a congeneric set of compounds using a structurally diverse reference compound indicates the potential to design new lead compounds using MSA.

A general QSAR for dihydrofolate reductase inhibition by 2,4-diaminotriazines based upon molecular shape analysis

A general quantitative structure-activity relationship (QSAR) is proposed to explain the 50% in vitro inhibition of dihydrofolate reductases from Walker 256 tumor, and/or L1210 leukemia cells, bovine liver, and rat liver by any reported 2,4-diaminotriazine. A maximum of four molecular descriptors are needed in the QSAR. Three of these descriptors characterize molecular shape and are determined from conformational analysis. The fourth descriptor is the sum of the water/octanol fragment constants for 3- and 4-substituents on the phenyl ring of a triazine molecule. The need for specific descriptors, and their corresponding linear or parabolic behavior in a correlation equation, depends upon the choice of the triazine compound data base, and the species source of the dihydrofolate reductase. Correlation coefficients, R, in the range 0.92 to 0.96 have been achieved for the QSAR equations derived from data bases containing compounds that had to be deleted in previous structure-activity studies.

A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis

A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis