Quantitative Structure-activity Correlations Research Articles

In Silico Investigations of Some Carbohydrate Derivatives: Pass Prediction, ADMET, QSAR, and Molecular Docking Studies against Pseudomonas aeruginosa

Carbohydrates are plentiful naturally occurring macromolecules that are crucial to a range of biological activities. Therefore, the focus of our research group has been on computational studies of previously synthesized methyl α-D-glucopyranoside (α-MGP) derivatives. To determine the chemical descriptors of the synthesized compounds, quantum chemical research was conducted using Gaussian09 and the DFT (density functional theory) calculations. Frontier molecular orbital features, electrostatics potential, and thermodynamic properties of these optimized compounds are investigated. PASS (prediction of activity spectra for substances) showed the excellent thermodynamic and antimicrobial properties of the designed α-MGP derivatives. The binding energy and binding strategies of certain bacterial proteins from Pseudomonas aeruginosa (3PBN, and 3PBS) were investigated using molecular docking simulations, and adequate binding affinity was reported. QSAR (quantitative structure-activity correlations) analysis found a better drug-likeness profile for all α-MGP derivatives, and pharmacokinetic prediction demonstrated an enhanced drug-likeness profile of α-MGP derivatives. Furthermore, by side chain alteration in the α-D-glucopyranoside sequence, these compounds can be thought of as strong antibacterial agents.

Carbonic anhydrase inhibitors. Part 41. Quantitative structure-activity correlations involving kinetic rate constants of 20 sulfonamide inhibitors from a non-congeneric series

A quantitative structure-activity relationship study is presented for 20 sulfonamide inhibitors of carbonic anhydrase. These drugs do not form a classical congeneric series, in that the only common factor is the sulfonamide group, which is attached to a variety of substituted aromatic and hetero-aromatic nuclei. The important factors were local factors such as Mulliken charge on atoms of the sulfonamide group, and global factors such as the size and shape of the molecule, its calculated frontier orbital energies, and its lipophilicity. Good correlations were obtained with the equilibrium constant and the kinetic association rate constant, but not with the kinetic dissociation rate constant.

Integration of graph theory and quantum chemistry for structure-activity relationships.

The objective of this article is to outline both graph-theoretically based and quantum chemically based structural indices of potential use in quantitative structure activity correlations. We consider graph-theoretical indices such as the connectivity index, topological index, Wiener index and molecular ID indices. Several structural and geometry-dependent indices can be derived from semiempirical and ab initio quantum calculations based on the charge densities, overlap matrices, frontier orbitals, molecular hardness, free valence, density matrices, quantum spectral difference indices, quantum spectral indices and bond matrices. Finally, the use of electrostatic potentials and charge densities for the prediction of reactive sites will be discussed.

Quantitative structure—Activity relationship of fluridone derivatives with phytoene desaturase

Structure-activity investigations were carried out with fluridone analogs which are inhibitors of the enzyme phytoene desaturase. The chemical modifications of the 21 bleaching compounds used were all positioned at the pyridinone ring. Inhibition of carotenoid biosynthesis was determined either with intact cells of the cyanobacterium Aphanocapsa or with isolated Aphanocapsa thylakoid membranes assaying inhibition of phytoene desaturation. Methyl was found to be a favorable N-substituent, and the aromatic nature of the heterocycle is not essential although the resulting piperidinone showed lower bleaching activity. Replacement of the keto group by either methoxy or dimethylamine resulted in lowered but still substantial inhibition. The corresponding thione or chloro derivatives were more or less inactive. Quantitative structure-activity correlations were calculated between inhibitory activity and physicochemical properties of the substituents at position 3 of the pyridinone ring. Regression analysis showed a significant correlation between cellular I 50 values and lipophilicity π and σ p. Using in vitro data the contribution of σ p to the regression was not significant.

The acute toxicity of pulse-dosed, para-substituted phenols to larval American flagfish ( Jordanella floridae): a comparison with toxicity to photoluminescent bacteria and predicted toxicity using log Kow

The acute toxicity of nine para-substituted phenols was determined using a pulse-exposure testing protocol and 8-day-old larval American flagfish ( Jordanella floridae). Relative tolerance was assessed by determining the 2-h pulse exposure concentration causing 20 and 50% mortality (PE LC 20 and PE LC 50) over the subsequent 94 h. Four bioassays were run for each phenol and yielded the following mean PE LC 20 values (mg 1 −1) in descending order of toxicity: p-aminophenol, 0.06; hydroquinone, 0.13; phenol, 0.70; p-nitrophenol, 0.81; p-cyanophenol, 3.0; p-chlorophenol, 3.3; p-hydroxyacetophenone, 4.2; p-hydroxybenzyl alcohol, 6.4; and p-hydroxybenzoic acid, 170. These toxicities did not correlate significantly with either previously reported toxicity values for the photoluminescent bacteria Photobacterium phosphoreum, or with the log octanol-water partition coefficient. For some of the compounds, however, sensitivities were quite close to previously reported rainbow trout chronic no-observed-effect concentrations based on continuous exposure. Caution is urged with respect to applying “low-level” biota techniques or simple quantitative structure-activity correlations such as K ow when attempting to predict the toxicity of specific chemicals to fish.

On characterization of three-dimensional structures

Molecular descriptors currently used in structure–property–activity studies are based on molecular graphs rather than on a structure as a three-dimensional object. Here we suggest a way to amend graph-theoretic invariants with additional geometric information, thereby providing new molecular descriptors for possible use in quantitative structure–activity correlations. In the approach we assume molecular structures embedded on a regular grid. As an illustration we consider first chains of different length embedded on graphite-like lattice. Subsequently, we consider all possible conformations of hexatriene. Although the cases considered here relate to graphite-like lattice, the approach is general and applies to embedings of molecules on three-dimensional lattices, or, in general, to molecules of arbitrary spatial conformations.

THE SYNTHESIS OF PHOSPHORAMIDOTHIOATES AND THEIR QUANTITATIVE STRUCTUREACTIVITY CORRELATIONS

O-Aryl O-ethyl N-isopropyl phosphoramidothioates (Ⅰ) have herbicidal activity. In order to study the relationship between structures and activities of these compounds, more than thirty compounds (Ⅰ) have been prepared by the reaction of O-aryl O-ethyl phosphorochloridothioates with isopropylamine in the presence of 40% NaOH at 0℃. The intermediates, phosphorochloridothioates, were prepared separately from a large excess of O-ethyl Phosphorodichloridothioate and various substituted phenols in the presence of 40% NaOH and a catalyrical amount of Et_3N at 0—5℃. As a result, higher purity and good yields were obtained.It was found that the activity of these compounds was highly dependent upon the substituents attached to the benzene ring with respect to the characteristic parameters π, E_s, σ and F by using Hansch's equation.It was indicated that hydrophobic (π), steric (E_s), and electronic (σ and F) effects of the substituents on the ring in those molecules seem to be of considerable importance in determining their biological activity.By replacing π with △R_m and a and F with △δ_p, respectively, in regression analysis a better correlation was obtained. Both △R_m and △δ_p were experimental data. The former was calculated from R_f measured with reversed-phase thin-layer chromatography and the latter was obtained from the difference between the chemical shifts of the ~(31)P NMR of compounds(Ⅰ) and that of the parent compound.

Structure‐activity relationships for nitrogen‐containing aromatic molecules

AbstractTwenty‐four nitrogen‐containing aromatic molecules, mono‐ and dicyclic homologs from each of 12 different analog sets, were studied to determine their relative acute static toxicities, monitored as population growth impairment to the ciliate Tetrahymena pyriformis. Quantitative structure‐activity correlations between the molecular descriptors log l‐octanol/water partition coefficient (log Kow) and log toxicity are reported. Using the complete data set the descriptor does not provide an adequate model for predictability. A scatter plot of log Kow versus log toxicity suggests two parallel linear correlations: one consisting of the more complex multiple H‐polar nitrogen‐containing compounds and the other with the single H‐polar and in‐ring substituted nitrogen‐containing compounds.

STRUCTURE-ACTIVITY RELATIONSHIPS FOR NITROGEN-CONTAINING AROMATIC MOLECULES

Twenty-four nitrogen-containing aromatic molecules, mono- and dicyclic homologs from each of 12 different analog sets, were studied to determine their relative acute static toxicities, monitored as population growth impairment to the ciliate Tetrahymena pyriformis. Quantitative structure-activity correlations between the molecular descriptors log l-octanol/water partition coefficient (log Kow) and log toxicity are reported. Using the complete data set the descriptor does not provide an adequate model for predictability. A scatter plot of log Kow versus log toxicity suggests two parallel linear correlations: one consisting of the more complex multiple H-polar nitrogen-containing compounds and the other with the single H-polar and in-ring substituted nitrogen-containing compounds.

Organic contaminants in the environment: Research progress and needs

An already large and rapidly increasing number of manmade organic contaminants is found to be present in environmental samples from around the world. However, the biological effects of many of these compounds are unknown. Traditional biological testing, albeit important, cannot be done on each chemical due to limitations of the available resources. Therefore, new avenues should be pursued to screen out the hazardous compounds for more intensive research. One of these avenues, quantitative structure-activity correlations, applies the existing knowledge to estimate the effects of other, structurally related compounds. In combination with a fast and cost-effective biological test, this method appears useful in solving both the existing backlog and future needs for information on the safety and environmental effects of new chemicals.

Quantitative structure-activity relationships of aromatic esters of 1-methyl-4-piperidinol as analgesics.

Substituted benzoic acid esters of 1-methyl-4-piperidinol showed analgesic activity when assayed by the mouse hot-plate methods, the more potent ones falling in the morphine-codeine range. To understand how substituents on the aromatic ring affect the analgesic potency, quantitative structure-activity correlations were carried out on a series of 44 derivatives. Among the various substituent parameters included in the study, Lortho (Length of ortho-substituents) and B1 (minimal width of substituents) or E8 at meta and para positions gave negative correlation with the potency, while lipophilicity (especially pi meta) and the ability of being a hydrogen-bond acceptor enhanced the potency. Based on the QSAR results, a substitution pattern of the phenyl group was defined for optimal activity. Implications on drug-receptor interactions and the possible binding mode of these compounds were discussed.

The ortho effect in quantitative structure—activity correlations

A procedure for assessment of the effects of o-substituents in physical-organic systems by means of linear combination of substituent parameters is described and its applicability to various data sets on reactivity and equilibrium is shown. The procedure seems to provide a physicochemical background to the quantitative analysis of structure—activity relationships for biologically active aromatic ortho compounds. The ortho effect in biological activity is analyzed in terms of a linear combination of the electronic parameter σ p and field-inductive F, hydrophobic π and steric E s parameters. Depending on the type of steric effect, other parameters may be used. The model is shown to be applicable to several biological activity data sets of aromatic pesticide congeners including o-substituted derivatives.

ChemInform Abstract: QUANTITATIVE STRUCTURE‐ACTIVITY CORRELATIONS OF RIFAMYCINS AS INHIBITORS OF VIRAL RNA‐DIRECTED DNA POLYMERASE AND MAMMALIAN α AND β DNA POLYMERASES

Chemischer InformationsdienstVolume 11, Issue 34 Natural Products ChemInform Abstract: QUANTITATIVE STRUCTURE-ACTIVITY CORRELATIONS OF RIFAMYCINS AS INHIBITORS OF VIRAL RNA-DIRECTED DNA POLYMERASE AND MAMMALIAN α AND β DNA POLYMERASES R. S. WU, R. S. WUSearch for more papers by this authorM. K. WOLPERT-DEFILIPPES, M. K. WOLPERT-DEFILIPPESSearch for more papers by this authorF. R. QUINN, F. R. QUINNSearch for more papers by this author R. S. WU, R. S. WUSearch for more papers by this authorM. K. WOLPERT-DEFILIPPES, M. K. WOLPERT-DEFILIPPESSearch for more papers by this authorF. R. QUINN, F. R. QUINNSearch for more papers by this author First published: August 26, 1980 https://doi.org/10.1002/chin.198034313Read the full textAboutPDF 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 onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume11, Issue34August 26, 1980 RelatedInformation

Quantitative structure-activity correlations of rifamycins as inhibitors of viral RNA-directed DNA polymerase and mammalian .alpha. and .beta. DNA polymerases

Twenty-two 3-substituted rifamycins were tested for inhibition of mammalian alpha and beta DNA polymerase and viral RNA-dependent DNA polymerase ("reverse transcriptase"). Quantitative structure--activity relationships (QSAR) were formulated for the three systems. Inhibition is linearly dependent on the partition coefficient and is highly favored by the presence of bulky hydrazones or oximes. None of these agents proved to be a selective or specific inhibitor of reverse transcriptase. A correlation in terms of log P and (log P)2 was obtained from data on a more closely related set of analogues from a published study. For murine reverse transcriptase, log P0 = 5.1.

Mapping of dihydrofolate-reductase receptor site by correlation with minimal topological (steric) differences

A procedure for obtaining the shape of (or part of the shape of) a receptor site cavity based on structures of molecules with known activities is outlined and applied to dihydrofolate reductase inhibitors. The procedure consists of determining the optimal standard for calculating the minimal topological (steric) differences (MTD, number of unsuperposable atoms when a molecule is superimposed over the standard). For a series of 15 diaminopyrimidines, substituted in position 5 with aliphatic, cyclo-aliphatic or arylic groups, the correlation of inhibitory power with MTD and π-Hansch hydrophobicity gives a coefficient r = 0.981, while correlating with π only, r = 0.767 is obtained. This procedure may be useful in obtaining quantitative structure-activity correlations for series of non-congeneric molecules, if there are no marked changes in polar groups.

Theory of linear equations as applied to quantitative structure-activity correlations.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTheory of linear equations as applied to quantitative structure-activity correlationsL. J. Schaad and B. A. Hess Jr.Cite this: J. Med. Chem. 1977, 20, 5, 619–625Publication Date (Print):May 1, 1977Publication History Published online1 May 2002Published inissue 1 May 1977https://doi.org/10.1021/jm00215a001RIGHTS & PERMISSIONSArticle Views47Altmetric-Citations9LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (737 KB) Get e-Alerts Get e-Alerts

Mode of action and quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic acid hydrazide type.

Quantitative structure-activity studies have been performed for a series of 2-substituted isonicotinic acid hydrazides by correlating electronic, steric, and lipophilic properties of the substituents with the biological activity date (MIC) from serial dilution tests with Mycobacterium tuberculosis (strain H 37 Rv). The reaction rates for the quaternization of 2-substituted pyridines with methyl iodide were also determined. The rate constants show a similar dependence on the steric and electronic effects of the substituents as the antibacterial activities of the corresponding pyridine-4-carboxylic acid hydrazides. The obtained correlations give evidence that the reactivity of the pyridine nitrogen atom is essential for the biological activity of 2-substituted isonicotinic acid hydrazides and seem to support the hypothesis that isonicotinic acid derivatives are incorporated into an NAD analogue.

Anti-Inflammatory Activity of para-Substituted N-Benzenesulfonyl Derivatives of Anthranilic Acid

Several para-substituted N-benzenesulfonyl derivatives of anthranilic acid were prepared and evaluated for anti-inflammatory activity using erythrocyte membrane stabilization and carrageenin-induced rat paw edema assays. N-p-Bromobenzenesulfonylanthranilic acid possessed greater activity than phenylbutazone in both assays. Quantitative structure-activity correlations employing the Hansch method were unsuccessful in the erythrocyte membrane stabilization assay. However, correlations were obtained in the rat paw edema assay, and it appears that the activity of these derivatives depends solely on the lipophilic character of the substituents on the benzenesulfonyl ring.