Finding key members in compound libraries by analyzing networks of molecules assembled by structural similarity.

Characterization of chemical libraries is an essential task in everyday chemoinformatics practice. This study describes some potential uses of network visualization and analysis methods to identify distinguished members of compound libraries. Molecules were ordered into networks by their structural similarity defined by molecular fingerprints. Various properties of such networks were examined. It was shown, that the correlation methods used to calculate the similarity between two structures radically determined the topology of networks. From the same set of molecules, the Russel-Rao and the Baroni-Urbani methods created sparser and denser networks, respectively, than using the Tanimoto method. Central nodes, corresponding to central compounds in the libraries, were determined for some example data sets. It was shown by the case of adenosine A1, A2, and dual antagonists that the methods used to identify central nodes could be divided into two groups: (1) centrality methods, exemplified by the centroid centrality, which could pick up structures that were the most similar to the largest number of other molecules and (2) group, exemplified by betweenness centrality, that could identify molecules that had intermediate structures between some homogeneous subsets of the library. The latter method gave significantly higher ranks to dual adenosine antagonists, hinting the suitability of this measure to identify molecules with multiple activities. Some practical applications of the method for clustering of and sample selection from chemical libraries are presented. In the frame of the study, a Jchem plug-in has been developed to the Cytoscape network visualization software, which makes the visual observation of molecular networks more convenient. The plug-in is included in the Supporting Information of the article for free usage.

An integrated database of flavonoids.

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Some of these molecules exhibit various physiological activities. Among existing drugs, there are a huge number of compounds bearing a flavonoid-related skeleton. Because of the relevance for pharmaceutical research, it would be beneficial to collect these compounds into a database. Recently, various databases of chemicals were compiled to help biological and/or chemical research, but no comprehensive database of flavonoids with chemical structures and physicochemical parameters, supposedly related to their activity, is available yet. The aim of this research was to merge the information about flavonoids of plant origin and flavonoids used as medicines into a database. Moreover, predictions of activities against various targets were performed using a virtual screening procedure to demonstrate a possible application of the database for pharmaceutical research.

Comparative analysis of binding energy of chymostatin with human cathepsin A and its homologous proteins by molecular orbital calculation.

Cathepsin A is a mammalian lysosomal enzyme that catalyzes the hydrolysis of the carboxy-terminal amino acids of polypeptides and also regulates beta-galactosidase and neuraminidase-1 activities through the formation of a multienzymic complex in lysosomes. Human cathepsin A (hCathA), yeast carboxypeptidase (CPY), and wheat carboxypeptidase II (CPW) belong to the alpha/beta-hydrolase fold family. They have structurally similar active-site clefts, but there are small differences in the amino acid residues comprising their active sites that might determine the substrate specificity and sensitivity to microbial inhibitors including chymostatin. To examine the selectivity and binding mechanism of chymostatin as to hCathA, CPY, and CPW at the atomic level, we analyzed the interaction energy between chymostatin and each protein quantitatively by semiempirical molecular orbital calculation AM1 with the continuum solvent model. We predicted the electrostatic repulsion between the P3 cyclic arginine residue of the inhibitor and the Arg344 in the S3 active subsite of hCathA. Genetic conversion of Arg344 of the wild-type hCathA to Ile also caused an increase in its sensitivity to chymostatin, which was correlated with the decrease in the interaction energy calculated with the molecular orbital method. The present results suggest that such molecular calculation should be useful for evaluating the interactions between ligands, including inhibitors and homologous enzymes, in their docking models.

Screening for new antidepressant leads of multiple activities by support vector machines.

Virtual screening was carried out against 21 biological targets related to depression by support vector machine classification using the same atom-type descriptors. The models were effective as 0.2-0.8 of theoretical enrichments of the external test data sets could be achieved, depending on the target. The set of predicted active molecules had large diversity and contained examples with high dissimilarity to the compounds of training sets. Filtering the database of known antidepressants by all 21 models it was found that on average compounds were classified active for 2.3 targets.

Approach to novel functional foods for stress control: 1. Toward structure-activity relationship and data mining of food compounds by chemoinformatics.

Over the past several decades, thousands of natural organic compounds have been isolated from foods, and the information about their structures and biological activities has been accumulated. Despite the long research history of food products and their potential great promise as a medicine and functional food, the systematic research and development have not been carried out extensively. For understanding of the comprehensive structure-activity relationship, we have developed the database system of flavonoids, which are frequently found in vegetables and fruits. We also plan to execute a virtual screening of flavonoids with antidepressant activity by using the database and an advanced chemoinformatic tool. In this section, we will briefly describe (1) flavonoid database and (2) virtual screening of antidepressant compounds.

Construction of a novel database for flavonoids.

Flavonoids are polyphenolic compounds that exist ubiquitously in foods of plant origin. Flavonoids show various interesting biological activities, such as removal of oxygen radical, anti-cancer action, improvement of high blood pressure, antibacterial, antibiotic and anti-allergy actions. So far, over 4000 structurally unique flavonoids have been isolated from plant sources. Recently, databases of chemicals have been utilized in to help chemical and biological researches, however the comprehensive database of flavonoids with information about structural, biological and physicochemical properties not yet available. We have constructed the integrated database of flavonoids for nutrition research.

Virtual screening models for finding novel antidepressants.

Virtual screening was carried out against various biological targets related to depression by support vector machine classification using the atom-type descriptors. The models were effective as over 75 and 95% of the molecules in external test datasets could be correctly classified, depending on target. Antidepressant compounds had predicted activity against 2.3 targets, on average. An introduction is given to virtual screening and the results of classification experiments are presented.

Connecting traditional QSAR and molecular simulations of papain hydrolysis--importance of charge transfer.

Molecular dynamics and full structure LocalSCF semi-empirical quantum mechanics calculations of receptor-ligand complexes were carried out to investigate structure-activity relationship for the papain hydrolysis of a series of N-benzoylglycine esters and reinterpret traditional QSAR descriptors using detailed structural information. A correlation of r(2)=0.694 was obtained and it was shown that the pattern of charge distribution on the ester group is different if charges of free or complex ligands or are analyzed. The results can help to understand how traditional QSAR descriptors, such as F or sigma, interacts with other electronic effects during complex formation.

Mechanism of preferential enrichment, an unusual enantiomeric resolution phenomenon caused by polymorphic transition during crystallization of mixed crystals composed of two enantiomers.

The mechanism of Preferential Enrichment, an unusual enantiomeric resolution phenomenon observed upon recrystallization of a series of racemic crystals which are classified as a racemic mixed crystal with fairly ordered arrangement of the two enantiomers, has been studied. On the basis of the existence of polymorphs and the occurrence of the resulting polymorphic transition during crystallization from solution, the mechanism has been accounted for in terms of (1) a preferential homochiral molecular association to form one-dimensional chain structures in the supersaturated solution of the racemate or nonracemic sample with a low ee value, (2) a kinetic formation of a metastable crystalline phase retaining the homochiral chain structures in a process of nucleation, (3) a polymorphic transition from the metastable phase to a stable one followed by enantioselective liberation of the excess R (or S) enantiomers from the transformed crystal into solution at the beginning of crystal growth to result in a slight enrichment (up to 10% ee) of the opposite S (or R) enantiomer in the deposited crystals, together with an enantiomeric enrichment of the R (or S) enantiomer in the mother liquor, and (4) a chiral discrimination by the once formed S (or R)-rich stable crystalline phase in a process of the subsequent crystal growth, leading to a considerable enantiomeric enrichment of the R (or S) enantiomer up to 100% ee in the mother liquor. The processes (3) and (4) are considered to be directly responsible for an enrichment of one enantiomer in the mother liquor. The association mode of the two enantiomers in solution has been investigated by means of (i) the solubility measurement and (ii) the number-averaged molecular weight measurement in solution by vapor pressure osmometry, together with (iii) the molecular dynamics simulation of oligomer models. The polymorphic transition during crystallization has been observed visually and by means of the in situ FTIR technique and DSC measurement. Both metastable and stable crystals have been obtained, and their crystal structures have been elucidated by X-ray crystallographic analysis of their single crystals.

Preferential enrichment: full crystallographic analysis of the unusual phenomenon in the mixed crystals' version.

Full characterization of the crystal structures of the racemate, nonracemate (20% ee), and pure enantiomer of [2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-bromobenzenesulfonate (NBMe3), which has successfully shown an unusual enantiomeric resolution phenomenon, "preferential enrichment," was achieved by means of X-ray crystallographic analysis and construction of the binary melting point phase diagram. The crystalline nature of the racemate is not a racemic compound but a fairly ordered mixed crystal composed of the two enantiomers. The crystal structure of the nonracemate (20% ee) is virtually identical with that of the racemate and similar to that of the pure enantiomer. The binary melting point phase diagram of NBMe3 is consistent with the nature of a mixed crystal composed of the two enantiomers.