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Biomedical subjects

Y C Martin

Publications and source records attributed to Y C Martin.

At least 19 recordsLinked to original sources
PubMed1999

Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein.

A new knowledge-based scoring function (PMF-score), implemented into the DOCK4 program, was used to screen a database of 3247 small molecules for binding to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was demonstrated that small, weakly binding molecules have, on average, higher computational scores than nonbinders and are enriched in the upper ranks of the computational scoring lists. In addition, the results obtained with the PMF scoring function were superior (by 30-120% larger enrichment factors) to those obtained with the standard force field score of DOCK4. The reliable ranking of small, weakly binding molecules offers new ways of designing building blocks in combinatorial libraries as well as SAR by NMR libraries with the increased chance of identifying suitable lead compounds for drug design.

Binding Sites↗
PubMed1999

A general and fast scoring function for protein-ligand interactions: a simplified potential approach.

A fast, simplified potential-based approach is presented that estimates the protein-ligand binding affinity based on the given 3D structure of a protein-ligand complex. This general, knowledge-based approach exploits structural information of known protein-ligand complexes extracted from the Brookhaven Protein Data Bank and converts it into distance-dependent Helmholtz free interaction energies of protein-ligand atom pairs (potentials of mean force, PMF). The definition of an appropriate reference state and the introduction of a correction term accounting for the volume taken by the ligand were found to be crucial for deriving the relevant interaction potentials that treat solvation and entropic contributions implicitly. A significant correlation between experimental binding affinities and computed score was found for sets of diverse protein-ligand complexes and for sets of different ligands bound to the same target. For 77 protein-ligand complexes taken from the Brookhaven Protein Data Bank, the calculated score showed a standard deviation from observed binding affinities of 1.8 log Ki units and an R2 value of 0.61. The best results were obtained for the subset of 16 serine protease complexes with a standard deviation of 1.0 log Ki unit and an R2 value of 0.86. A set of 33 inhibitors modeled into a crystal structure of HIV-1 protease yielded a standard deviation of 0.8 log Ki units from measured inhibition constants and an R2 value of 0.74. In contrast to empirical scoring functions that show similar or sometimes better correlation with observed binding affinities, our method does not involve deriving specific parameters that fit the observed binding affinities of protein-ligand complexes of a given training set. We compared the performance of the PMF score, Böhm's score (LUDI), and the SMOG score for eight different test sets of protein-ligand complexes. It was found that for the majority of test sets the PMF score performs best. The strength of the new approach presented here lies in its generality as no knowledge about measured binding affinities is needed to derive atomic interaction potentials. The use of the new scoring function in docking studies is outlined.

Algorithms↗
PubMed1998

Computational methods in molecular diversity and combinatorial chemistry.

Molecular diversity, combinatorial chemistry and automated synthesis are helping usher in a new age in medicinal chemistry. The tools and practices of computational chemistry and molecular modeling are rising to the challenges and opportunities presented by the current trends in drug discovery and design. Recent advances include a number of new and meaningful measures of molecular diversity and the use of genetic algorithms to help design diverse libraries.

Algorithms↗
PubMed1998

An evaluation of structural descriptors and clustering methods for use in diversity selection.

An evaluation of the suitability of a number of structural descriptors and clustering methods for use in diversity selection is presented. The methods are compared by their success in simulated biological activity predictions. The results suggest that simple 2D structural descriptors are particularly effective and that hierarchical clustering methods are superior to the non-hierarchical methods traditionally used for diversity related tasks. Results are presented which suggest that the difference in the utility of the descriptors can be accounted for by the different extent to which each encodes information relevant to the forces of ligand-receptor binding.

Algorithms↗
PubMed1997

Designing combinatorial library mixtures using a genetic algorithm.

The design of combinatorial mixture libraries should take account of a number of factors. This paper describes the application of a genetic algorithm to optimizing the diversity of libraries while minimizing the effort that will be needed to deconvolute the biological hits by mass-spectroscopic techniques. It differs from previous applications of genetic algorithms to combinatorial library design in that each chromosome encodes an entire library with the result that properties of the library are optimized. Our method is such that it is easily extensible to optimizing the distributions of any number of physical or other properties of the library. The method allows for the combinatorial constraint inherent in mixtures that every substituent at each diversity site must occur in combination with every substituent at every other site. We present results showing that the genetic algorithm can produce good library designs in timely manner.

Algorithms↗
PubMed1996

Novel 3-Pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors.

Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

Alkaloids↗
PubMed1995

PLS analysis of distance matrices to detect nonlinear relationships between biological potency and molecular properties.

Although the statistical method of partial least squares (PLS) is widely used for the analysis of the relationship between molecular properties and biological potency, it is recognized that PLS detects only linear relationships. We tested two types of properties: simulated univariate data and electrostatic molecular field as a function of Hammett sigma constants. In both cases we compared relationships in which the function is linear, asymptotic, or rises to an optimum and then falls. We found that PLS analysis of the matrix of the distances between every pair of compounds detects all three types of relationships with the same quality of cross-validation. The successful application of the method requires that the distance matrices be constructed such that each contains only information about one property (for example, the electrostatic field around the functional group of interest). Carbo and Hodgkin similarities perform less well than distances.

Models, Chemical↗
PubMed1994

Quantitative structure-activity relationships of 5-lipoxygenase inhibitors. Inhibitory potency of pyridazinone analogues.

Quantitative structure-activity relationships (QSAR) of 72 1-phenyltetrahydropyridazin-3(2H)-one (I) analogues are examined for the inhibitory potency (IC50) of 5-lipoxygenase in a broken cell. The potency is increased by lipophilic substituents at the 3'- and 4'-positions. Substituents with positive F value at the 4'-position also increase the potency, while substituents at the 3'-position with a positive R value decrease it. The potency also decreases as the size of the 2'- and/or 4'-substituents increases. Thioketone analogues are about 5 times more potent than the corresponding carbonyl analogues.

Animals↗
PubMed1993

Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships and comparative molecular field analysis.

Quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed: log SOSIP = -33.1qc2 + 1.00 log P - 1.50Isat - 1.19MR - 0.76I5,6 - 3.76; n = 40, r = 0.900, s = 0.475. The QSAR model clearly reveals three important factors, namely, electronic (qc2), hydrophobic (log P) and steric (MR, Isat, I5,6) contributing toward the genotoxic activity of this class of compounds. qc2, the charge on the c2 atom attached to the NO2 group, supports a furan ring opening mechanism in explaining the genotoxicity. The finding of the coefficient of 1 with log P conforms to our previous findings with several different classes of mutagens acting on different systems. CoMFA analysis clearly demonstrates its potential in unraveling the steric features of the molecules through contour maps. The CoMFA cross-validated model also supports the importance of the electronic factor. It could not reveal any hydrophobic influence because the interaction energies of the CH3 and H2O probes are collinear. QSAR (classical) and CoMFA, if used judiciously, may complement each other and enhance the applicability of SAR in drug design.

Escherichia coli↗
PubMed1993

A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists.

In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optimize all low-energy conformations by any suitable method. For each conformation we then use ALADDIN to calculate the location of points to be considered as part of the superposition. These points include atoms in the molecule and projections from the molecule to hydrogen-bond donors and acceptors or charged groups in the binding site. These positions and the relative energy of each conformation are the input to our new program DISCO. It uses a clique-detection method to find superpositions that contain at least one conformation of each molecule and user-specified numbers of point types and chirality. DISCO is fast; for example, it takes about 1 min CPU to propose pharmacophores from 21 conformations of seven molecules. We typically run DISCO several times to compare alternative pharmacophore maps. For D2 dopamine agonists DISCO shows that the newer 2-aminothiazoles fit the traditional pharmacophore. Using site points correctly identifies the bioactive enantiomers of indoles to compare with catechols whereas using only ligand points leads to selecting the inactive enantiomer for the pharmacophore map. In addition, DISCO reproduces pharmacophore maps of benzodiazepines in the literature and proposes subtle improvements. Our experience suggests that clique-detection methods will find many applications in computational chemistry and computer-assisted molecular design.

Algorithms↗
PubMed1993

Computer design of bioactive compounds based on 3-D properties of ligands.

3-D database searching has many uses for a medicinal chemist. It can aid in the design of compounds to probe or to mimic the bioactive conformation of a natural ligand or to fit a hypothetical or experimental structure of a binding site. It also can identify existing molecules that meet these criteria--new uses for old molecules. If one has a database of active compounds, 3-D searching can validate or refute a pharmacophore hypothesis. The CoMFA method of 3DQSAR can be used to forecast the potency of the designed analogs. Also, the integration of CoMFA and 3-D searching concepts provides a framework for the design of a good series for CoMFA. In addition, CoMFA 3DQSAR coefficients provide a model of the binding site to facilitate the design of compounds that fit the pharmacophore and do not hit sterically unfavorable regions.

Animals↗
PubMed1991

Direct prediction of dissociation constants (pKa's) of clonidine-like imidazolines, 2-substituted imidazoles, and 1-methyl-2-substituted-imidazoles from 3D structures using a comparative molecular field analysis (CoMFA) approach.

The applicability of a comparative molecular field analysis (CoMFA) method to reproduce and predict the pKa values of 28 clonidine-like imidazoline analogues and 16 2-substituted imidazoles has been investigated with the GRID force field. Molecular fields calculated with an H+ probe and AM1 partial atomic charges produced a correlation with a small standard deviation and a high correlation coefficient with cross validation. It was concluded that the CoMFA treatment of electrostatic effects is suitable for predicting pKa values and thus for the examination of the electronic effects in 3D quantitative structure-activity relationships.

Clonidine↗
PubMed1990

Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives.

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.

Animals↗
PubMed1990

Inhibitors of immune complex-induced inflammation: 5-substituted 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile derivatives.

A number of 5-substituted 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile analogues have been studied as inhibitors of the rat pleural reverse passive Arthus reaction, and quantitative structure-activity relationships (QSAR) of these analogues have been examined. The QSAR equations indicate that hydrophilic substituents at the 5-position produce more potent compounds, while electron-releasing groups decrease activity. The results supplement QSAR data we previously obtained from the dermal reverse passive Arthus reaction.

Animals↗
PubMed1989

Inhibitors of immune complex-induced inflammation: 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile derivatives.

The octanol-water partition coefficients (log P) and the dissociation constants (pKa) of 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile analogues have been determined, and quantitative structure--activity relationships (QSAR) of the analogues as inhibitors of immune complex-induced inflammation have been studied. A significant correlation is observed between log P and pi substituent constants, and between pKa and inductive-field (F) and resonance (R) constants. The QSAR equations indicate that smaller substituents both at the 5-position and/or at the side chain tend to make the compound more potent, while an electron-withdrawing group at the side chain tends to make the compound less potent. The predicted potencies of 14 of 18 additional monosubstituted and all six disubstituted analogues agree reasonably well with the observed activities.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

ALADDIN: an integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric, steric, and substructure searching of three-dimensional molecular structures.

ALADDIN is a computer program for the design or recognition of compounds that meet geometric, steric, and substructural criteria. ALADDIN searches a database of three-dimensional structures, marks atoms that meet substructural criteria, evaluates geometric criteria, and prepares a number of files that are input for molecular modification and coordinate generation as well as for molecular graphics. Properties calculated from the three-dimensional structure are described by either properties calculated from the molecule itself or from the molecule as compared to a reference molecule and associated surfaces. ALADDIN was used to design analogues to probe a bioactive conformation of a small molecule and a peptide, to test alternative superposition rules for receptor mapping of the D2 dopamine receptor, to recognize unexpected D2 dopamine agonist activity of existing compounds, and to design compounds to fit a binding site on a protein of known structure. We have found that series designed by ALADDIN show much more subtle variation in shape than do those designed by traditional methods and that compounds can be designed to be very close matches to the objective.

Binding Sites↗