bluuebunny/crossref_metadata_2025_split huggingface dataset:
Theoretical Approximation to the Reaction Mechanism of Adenosine Deaminase
Authors: Orozco Modesto , Lluis Carmen , Mallol Josefa , Canela Enric I. , Franco Rafael 
Published: October 2006

AbstractA quantum chemistry‐based strategy has been used for obtaining correlations between electronic parameters and the relative activity of some adenosine analogues that are substrates of adenosine deaminase. A semi‐empirical method (MOPAC program using AM1 hamiltonian) has been used for designing a molecule, alternative to adenosine, and less expensive from a computational point of view. It has been demonstrated that 9‐hydroxymethyl‐adenine effectively mimics adenosine behaviour in terms of electronic characteristics of purine ring. The parameters studied were net charge on N1 and C6, global (∑Q) charge over pyrimidine and purine rings and orbital frontier parameters over C6 and N1. For analogues of adenosine and formycin in which ribose were substituted by a hydroxymethyl group, correlations between these parameters and the log Vm of reaction (collected from experimental data) with adenosine deaminase have been studied. The results indicate that there is an increase in the maximum rate of deamination Vm when the negative net charge over the pyrimidine and purine rings also increases. In view of the results obtained with different forms (neutral, protonated at N1 and hydroxylated at C6) of adenosine and formycin analogues it is suggested that the protonation at N1 is the rate limiting step of the reaction catalyzed by adenosine deaminase.
Conformational Analysis on Calcium Channel Active Diphenylalkylamines, Diphenylbutylpiperidines, Phenylalkylamines, and Perhexiline
Authors: Höltje Hans‐Dieter , Maurhofer Ernst 
Published: October 2006

AbstractA conformational analysis on calcium antagonists with diphenylalkylamine and diphenylbutylamine structure was performed based on force field calculations. Superposition of all energetically permitted conformations of all compounds under study led to the development of a common pharmacophore for both diphenylalkylamines (DPAAs) and diphenylbutylpiperidines (DPBPs). The pharmacophore consists of a – under physiological conditions protonated – nitrogen atom and three aromatic substructures. Conformational calculations on the verapamil derivative S( — )‐D595 and perhexiline showed that both substances possibly also interact with the DPAA/DPBP‐receptor.
Principles of Method Selection in Partition Studies
Authors: Hersey Anne , Hill Alan P. , Hyde Richard M. , Livingstone David J. 
Published: October 2006

AbstractAn integrated set of experimental methods is described which allows the determination of octanol/water partition coefficients for compounds of diverse structural type having log P values in the range – 1.3 to +4.6. This set has the advantage over a single technique of extending the scope and/or efficiency of log P measurement. A series of defined procedures for selecting the most appropriate method for a particular compound is described.The methods, which are all modifications of established techniques, are described in detail. The “Filter Chamber” technique is a quick and accurate method for log P measurement in the range ˜ −1.3 to +2.8. The “Spectrophotometric pH Profile” allows the “Filter Chamber” range to be extended to ˜ +4.6 by measurement of the extent of partitioning at pH values where the compound is partially ionised. The third technique, “Potentiometric Partition”, relies on potentiometric rather than spectrophotometric detection and hence has applications in determination of the log P of compounds with no chromophore. Each method is exemplified by measurements on simple organic molecules having known pKa and log P values.
Quantitative Structure‐Activity Relationship Studies on a New Class of Antihypertensive Agents: Derivatives of 3‐Aryl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[4,3‐c]pyridine
Authors: Singh P. , Sharma R. C. 
Published: October 2006

AbstractThe quantitative structure‐activity relationship (QSAR) has been studied for the derivatives of 3‐aryl‐4,5,6,7‐tetrahydropyrazolo[4,3‐c]pyridine for their in vitro ability to displace [3H]prazosin. The physicochemical parameters, hydrophobic (π), and electronic (σ), and the structural parameter, van der Waals volume (Vw) are found to be significantly correlated with the displacement activity of these compounds.
Hydrophobicity of N‐Acetyl‐Di‐ and Tripeptide Amides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters
Authors: Akamatsu Miki , Okutani Shin‐Ichi , Nakao Kazuya , Hong Nam Joo , Fujita Toshio 
Published: October 2006

AbstractThe log P value of 53 N‐acetyl‐di‐ and tripeptide amides composed of amino acids having unionizable side chains was measured in a 1‐octanol/pH 7.0 aqueous buffer system. The factors governing the variations in the log P value among these protected peptides were quantitatively analyzed to formulate a correlation equation with free‐energy‐related physicochemical and substructural parameters. The log P value was governed by the sum of the hydrophobicity of side chains and the backbone as well as by the steric effects of side chain substituents on the relative solvation of the backbone CONH groups. The log P value was found to decrease by 0.6 log unit for the peptide bond, other factors being equal. For amino acids with polar side chains, the log P value was also affected by the “polar proximity factor” and/or intramolecular hydrogen bond formation in a way similar to that of zwitterionized peptides reported previously.
A new Approach to Active‐Site Binding Analysis. Inhibitors of Acetylcholinesterase
Authors: Magee Philip S. 
Published: October 2006

AbstractReceptor site binding is shown to be localized in selected atoms or substructures with relatively minor contributions from the remaining molecular framework.Related compounds can be overlayed to form a lowest common structure or hyper‐molecule that defines every possible binding site for the series. Any attempt to analyze binding data on an atom‐by‐atom basis would clearly fail if all or most of the positions were involved in the energetics. In most data sets, analysis becomes feasible when most of the variance depends on a minority of the total occupied positions. This appears to be the case in most of the sets analyzed to date, providing us with a unique opportunity. By using atomic descriptors to model lipophilicity, London forces, steric repulsion and charge interactions, the binding site can be mapped by regression analysis. Each important site of interaction and the nature of the binding force can be clearly identified. This procedure provides a statistical method based on measured data that fully complements the visual fitting of modeled drugs into defined receptor sites by computer graphics. It has enormous potential for analysis of drug, agrochemical and toxicological binding data where crystallized enzymes and fully defined sites are unknown and may long remain so.The method is illustrated by examples drawn from acetylcholinesterase receptor site binding.
Further Comparative Studies of Fragment Weighting Schemes for Substructural Analysis
Authors: Ormerod Ann , Willet Peter , Bawden David 
Published: October 2006

AbstractThis paper considers the use of fragment weighting schemes for substructural analysis studies. Experiments are reported using 2‐D and 3‐D substructural descriptors with both small and large datasets for which qualitative activity data are available. The results support previous work in suggesting the potential of probabilistic models of weighting first used in studies of text retrieval.
QSAR on Substituted Salicylamides Using with Implementation of 3D MEP Descriptors
Authors: Norinder Ulf , Högberg Thomas 
Published: October 2006

AbstractA QSAR analysis of the [3H]spiperone binding affinity of 25 mono‐ and disubstituted salicylamides having F, Cl, Br, Me and Et substituents in the 3‐ and 5‐positions have been done with PLS (partial least squares in latent variables) method. Besides descriptors for size and lipophilicity, a large number of theoretically derived descriptors, i.e. polarizability, charge and molecular electrostatic potential (MEP), were used. The partial charges and the 3‐D MEPs were calculated using GAUSSIAN 80 at the STO‐3G level on model compounds lacking the pyrrolidine side‐chain. The MEPs at the van der Waals distance and at a larger distance corresponding to 3.0 Å from the aromatic plane were converted to point charges centered at the heavy atoms. The main component t1 explains 71% of the observed variance in biological activity and with inclusion of two minor components t2 and t3 a total of 88% explained variance is obtained. The size, lipophilicity and electronics of the 3‐substituent are of major importance. The MEP descriptors at the 3.00 Å distance also influence the activity despite the fact that the gross behaviour of the 2‐D MEPs was highly variable with no apparent correlation with D‐2 activity. The present study does not fully support current MEP pharmacophores on closely related compounds.
Model‐based LFER parameters and QSAR of Ligand β‐Adrenoceptor Interactions II. Estimation and QSAR of Agonistic Potency and Receptor Affinity in a Series of β‐Adrenergic phenethanolamines
Authors: Dove Stefan , Franke Rainer 
Published: October 2006

AbstractBased on an equilibrium model of ligand‐β‐adrenoceptor interactions and β‐adrenergic effectuation presented in a preceding paper, LFER‐related biological parameters to characterize affinity to the receptor and agonistic potency, respectively, are derived for a series of 44 phenethanolamines from measured apparent dissociation constants, KL, and intrinsic activities αACof adenylate cyclase activation. Both parameters result from a decomposition of pKLinto pKL= pKD+ log (1 + K*). Fragment regression analysis of pKLwas used for a preceding separation of the maximal contribution of agonistic interactions to apparent affinity. The log (1 + K*) scale was then estimated as logit transformation of αAC. Hansch analyses of log (1 + K*) and pKDlead to a clear separation of molecular features like substituent positions and interaction types responsible for agonistic potency and affinity, respectively. Thus, both parameters are proved to be of practical value, particularly as the resulting regression coefficients in Hansch equations are directly related to energy contributions of “basic” interaction events.
A Fragmental Code Usable for Automatic Attribution of Lipophilicity Atomic Constants
Authors: Dubost J. P. Croizet F. , Audry E. Langlois M. H. 
Published: October 2006

AbstractA flow chart is described for building a fragmental code including the same information as that contained in the fragmental graph defined by Broto and Coll. A method is then computed to automatically attribute the lipophilicity fragmental constants. This very fast method may be used to establish the Molecular Lipophilicity Potential or Autocorrelation Lipophilicity Vector, and to calculate the log P of a molecule.
A QSAR Model of Teratogenesis
Authors: Gombar Vijay K. , Borgstedt Harold H. , Enslein Kurt , Hart Jeffrey B. , Blake Benjamin W. 
Published: October 2006

AbstractFour related QSAR models of teratogenesis in experimental animals have been developed: one each for heteroaromatic, carboaromatic, alicyclic and acyclic compounds. The numbers of compounds in these models range from 40 (for the alicyclic model) to 144 (for the carboaromatic model). As determined by cross‐validation using the leave‐one‐out, or jackknife, technique, the accuracy of the models in discriminating between teratogens and non‐teratogens ranges from 92.4% to 96%.A single overall assessment of experimental teratogenesis was chosen as the biological endpoint; taking into account such factors as dosage, maternal toxicity, and affected organ systems remain to be subjects of further studies.
The Antibacterial Activity of Quinolones against E. Coli: A Chemometric Study
Authors: Bonelli Daniela , Cechetti Violetta , Clementi Sergio , Cruciani Gabriele , Fravolini Arnaldo , Savino Angela F. 
Published: October 2006

AbstractA chemometric approach based on multivariate calibration and design in latent variables permits one to rationalize the antibacterial activity of quinolones against gram negative bacteria, ranking the relative importance of individual structural features, and suggesting a new active structure.
Multivariate Structure‐Activity Relationships Analysis of Fungicidal and Herbicidal Thiolcarbamates Using Partial Least Squares Method
Authors: Miyashita Yoshikatsu , Ohsako Hiroyuki , Takayama Chiyozo , Sasaki Shin‐Ichi 
Published: October 2006

AbstractEighty‐three thiolcarbamates with fungicidal and herbicidal activities have been analyzed by a partial least squares (PLS) method. A three component PLS2 model based on 5 physicochemical descriptors explains 75.6% of the fungicidal and herbicidal activity data and is highly significant according to the leave‐one‐out procedure. The interpretation of structural requirements for the compounds with both more potent fungicidal and herbicidal activities is quite easy. Candidate thiolcarbamates with both fungicidal and herbicidal activities were proposed based on the PLS2 model. The PLS2 method has a great advantage that it can handle structural descriptor data X and multivariate activity data Y and get a total picture of relationships between X and Y blocks.
A Simple Model‐Based Function for Description of Non‐Linear Bioactivity‐Hydrophobicity Profiles
Authors: Baláž ŠTefan , Wiese Michael , Seydel Joachim K. 
Published: October 2006

AbstractA novel description of the relationship between bioactivity and hydrophobicity, log(1/ic) = AlogP – BP+const (ic is the isoeffective concentration and P is the partition coefficient) is derived from a model for drug disposition. The function fits experimental bioactivity‐hydrophobicity profiles with a linear ascending part and a sudden drop in bioactivity after reaching the break‐point equally well as the bilinear equation and better than parabola. Due to its simplicity and fast optimization of the adjustable parameters by linear regression analysis the function is especially suitable for the use in multivariable models.
Complete Thermodynamic Description of H‐Bonding in the Framework of Multiplicative Approach
Authors: Raevsky Oleg A. , Grigor'ev Veniamin Yu. , Kireev Dmitri B. , Zefirov Nicolai S. 
Published: October 2006

AbstractA complete thermodynamic description of H‐bonding for drug design is proposed. The approach is based on applicability of multiplicative principle to enthalpy (ΔH) and free energy (ΔG) of complex formation by means of Ed(Ea) and Cd(Ca) factors:

Where Ed(Ea) and Cd(Ca) characterize the proton donor (acceptor) ability of compounds. The estimation of E and C values for 163 proton donors and 195 proton acceptors was done, making it possible to predict ΔH and ΔG for 31785 reactions. The comparison of these data with experimental ones for 936 reactions was carried out:

The substituent effect on H‐bonding ability of compounds was considered. It was established that varying of substituents at active sites can alter its proton donor (acceptor) properties over a wide range of Ed(E3, cd(ca) with sufficient overlap between values of factors corresponding to different types of active sites. One could propose this approach to be applied to quantitative estimation of thermodynamic functions of H‐bonding in substrate‐receptor complexes; also for QSAR modelling, where E and C or its linear combination might be used as molecular descriptors characterizing quantitatively the relative H‐bonding ability of biologically active compounds. The second type of applications is used by the authors when modelling QSAR by means of the program package CLARAS (Classification and Recognition of Active Structures).
The Importance of Drug‐Membrane Interaction in Drug Research and Development
Authors: Seydel J. K. , Albores Velasco M. , Coats E. A. , Cordes H. P. , Kunz B. , Wiese M. 
Published: October 2006

AbstractThe importance of the interaction of drug molecules with membranes is discussed. The first two examples use the interaction of benzylpyrimidines with membranes of sensitive and resistant E. coli. This leads to a partial inactivation due to binding and to a change in mechanism of action, respectively. Another example deals with the interaction of amphiphilic benzylamines with artificial bilayers which lead to a change in conformation. The neuroleptic activity of Flupirtin derivatives could be described by the degree of interaction with bilayers quantified by NMR technique and a newly developed HPLC technique. Finally the interaction of amphiphilic drugs with membranes, possibly responsible for reversal of multidrug resistance in tumor and malaria therapy, is discussed.
Dipolarity and Partition Coefficient of Solvents, Drugs and Chemicals+
Authors: Lien Eric J. , Gao Hua , Wang Fengzhen , Shinouda Hakim G. 
Published: October 2006

AbstractThe parameters sometimes used to describe relative polarity of the solvents are dielectric constant (e) and partition coefficient (log P). Both of them have their limitations in terms of assessing relative solubilities of various organic/inorganic compounds in solvents commonly used. In an attempt to rectify this problem, we propose to use a new term “relative dipolarity (Dr)” which is defined as Dr = μ · M/L, and a two‐dimensional Log P‐Dr plot to classify all solvents from nonpolar to polar. We have found that among the single parameters examined Dr is the best single parameter to assess the relative polarity of the commonly used solvents. Dr also correlates better (than μ or e) with Log P. We have analyzed the relationship between Log P values of 25 solvents and their physicochemical parameters including molecular weight (MW), maximum hydrogen‐bond ability (HBm), and either Dr, μ or e. The Log Poct/w values of 110 disubstituted benzenes are also very well correlated with parameters including MW, μ (or μ1 and μ2 of the substituent group dipole moments), HBm (or HBa as hydrogen‐bond acceptor and HBd as hydrogen‐bond donor).
3D‐Quantitative Structure‐Activity Relationships: Describing Hydrophobic Interactions Directly from 3D Structures Using a Comparative Molecular Field Analysis (CoMFA) Approach
Authors: Kim Ki Hwan 
Published: October 2006

AbstractA method of describing hydrophobic interactions directly from 3D structures in 3D Quantitative structure‐activity relationships (QSAR) has been investigated. Molecular fields calculated with a H2O probe and the GRID force field using a comparative molecular field analysis (CoMFA) approach yield excellent correlations with significant cross‐validation. The results indicate that the CoMFA approach of describing hydrophobic interactions using a H2O probe is an excellent methodology for describing the corresponding effects in 3D QSAR studies.
A Principal Component and Cluster Significance Analysis of the Antiparasitic Potency of Praziquantel and some Analogues
Authors: Ordorica M. A. V. , Velázquez M. L. M. , Ordorica J. G. V. , Escobar J. L. V. , Lehmann P. A. F. 
Published: October 2006

AbstractThe cestocidal and schistocidal activities of praziquantel and 13 analogues were studied by using principal component and cluster significance analysis, together with potential function classification techniques. It was found that calculated size related properties and dipole moment significantly grouped the more active compounds, indicating their importance for activity. These results are compatible with the existence of a recognition site which mediates their antiparasitic activity and whose cavity surface must be almost exactly complementary to the pharmacophoric surface of praziquantel.
QSAR of Fungicidal Δ3‐1,2,4‐Thiadiazolines. Reactivity‐Activity Correlation of SH‐Inhibitors
Authors: Nakayama Akira , Hagiwara Kenji , Hashimoto Sho , Shimoda Susumu 
Published: October 2006

AbstractStructure‐activity relationships of fungicidal Δ3−1,2,4‐thiadiazolines were investigated by using molecular orbital (MO) calculations. Semiempirical MO calculations by MNDO‐PM3 method suggested that the reactivity of HOMO at the sulfur atom in the thiadiazoline ring is important to inhibit SH‐enzymes. In order to quantify the reactivity of the thiadiazolines, we defined an index, R(1), which is the electron density of HOMO at the sulfur divided by the orbital energy of HOMO. The fungicidal activity against cucumber downy mildew highly correlated with the R(1) index and hydrophobicity of molecule. The significance of R(1) and its square term in the QSAR equations suggested that a suitable range of reactivity is required to control the plant disease through the inhibition of SH‐enzymes.
A QSAR Approach for Estimating the Aquatic Toxicity of Soft Electrophiles [QSAR for Soft Electrophiles]
Authors: Veith Gilman D. , Mekenyan Ovanes G. 
Published: October 2006

AbstractThis work demonstrated that descriptors of soft electrophilicity for aromatic chemicals such as average superdelocalizability and LUMO energy could be used together with the hydrophobicity descriptor, log P, to explain the variation of acute toxicity of substituted benzenes, phenols, and anilines to fish. The hydrophobicity and soft electrophilicity descriptors were shown to be orthogonal for the 114 chemicals studied. For proelectrophiles, the structure‐toxicity relationships accurately predict toxicity when the stereoelectronic parameters were computed for the metabolic activation products. The QSAR for acute toxicity using these molecular descriptors defines a toxicity plane which includes several modes of toxic action.Type (I) narcotics are chemicals located in the region of low reactivity where toxicity varies with hydrophobicity alone. Type (II) narcotics are more toxic than type (I) narcotics at similar values of log P, and the increase can be explained by stronger electronic interactions with cellular soft nucleophiles. Highly reactive soft electrophiles which have dissociating protons such as 2,4,‐dinitrophenol produce symptoms of respiratory uncouplers. Those without dissociating protons produce symptoms of reactive toxicity consistent with covalent binding.
QSAR and Molecular Modelling for a Series of Isomeric X‐Sulfanilamido‐1‐phenylpyrazoles
Authors: Koch A. , Seydel J. K. , Gasco A. , Tironi C. , Fruttero R. 
Published: October 2006

AbstractThe influence of large substituents in o‐, m‐ and p‐positions of the phenyl ring of isomeric 3‐, 4‐ and 5‐sulfanilamido‐1‐phenylpyrazoles on their inhibitory effect against E.coli derived dihydropteroic acid synthase and whole cell E.coli has been studied. According to their pKa values, the 3‐ and 5‐series show high antibacterial activity while the 4‐series displays feeble inhibitory activity. In the 3‐series the variation in MIC is explained by differences in pKa (Hammett σ) and molecular weight (MW) or substituent surface respectively, whereas in the 5‐series steric effects of substituents in the o‐position of the 1‐phenyl ring and MW describe the differences in whole cell activity. In the cell‐free system the inhibitory activity depends for the 3‐series solely on pKa or Hammett σ, respectively, and in the 5‐series, where the derivatives are almost completely ionized, the variation is solely explainable by the steric effect of the substituents in o‐position. The steric effect of o‐substituents in the 5‐series has been studied and explained by NMR‐ and molecular modelling techniques. The observed differences in electronic effects of substituents comparing the 3‐ and 4‐series with the 5‐series could be explained by the results of quantum chemical calculations.