Mining and visualizing large anticancer drug discovery databases

In order to find more effective anticancer drugs, the U.S. National Cancer Institute (NCI) screens a large number of compounds in vitro against 60 human cancer cell lines from different organs of origin. About 70,000 compounds have been tested in the program since 1990, and each tested compound can be characterized by a vector (i.e., "fingerprint") of 60 anticancer activity, or -[log(GI50)], values. GI50 is the concentration required to inhibit cell growth by 50% compared with untreated controls. Although cell growth inhibitory activity for a single cell line is not very informative, activity patterns across the 60 cell lines can provide incisive information on the mechanisms of action of screened compounds and also on molecular targets and modulators of activity within the cancer cells. Various statistical and artificial intelligence methods, including principal component analysis, hierarchical cluster analysis, stepwise linear regression, multidimensional scaling, neural network modeling, and genetic function approximation, among others, can be used to analyze this large activity database. Mining the database can provide useful information: (a) for the development of anticancer drugs; (b) for a better understanding of the molecular pharmacology of cancer; and (c) for improvement of the drug discovery process.     

Advanced exact structure searching in large databases of chemical compounds

Efficient recognition of tautomeric compound forms in large corporate or commercially available compound databases is a difficult and labor intensive task. Our data indicate that up to 0.5% of commercially available compound collections for bioscreening contain tautomers. Though in the large registry databases, such as Beilstein and CAS, the tautomers are found in an automated fashion using high-performance computational technologies, their real-time recognition in the nonregistry corporate databases, as a rule, remains problematic. We have developed an effective algorithm for tautomer searching based on the proprietary chemoinformatics platform. This algorithm reduces the compound to a canonical structure. This feature enables rapid, automated computer searching of most of the known tautomeric transformations that occur in databases of organic compounds. Another useful extension of this methodology is related to the ability to effectively search for different forms of compounds that contain ionic and semipolar bonds. The computations are performed in the Windows environment on a standard personal computer, a very useful feature. The practical application of the proposed methodology is illustrated by several examples of successful recovery of tautomers and different forms of ionic compounds from real commercially available nonregistry databases.     

Tautomerism in alloxan

Ab initio STO-3G, 3-21G and 6-31G calculations have been used to investigate the energetics of the tautomerism in alloxan. The geometries of the tautomers have been fully optimized at STO-3G level. The results indicate that tautomerism in alloxan in the vapour is highly unlikely, the trioxo structure being by far the most stable structure. The population analysis of the alloxan anion gives evidence that the preferred protonation site is offered by the central oxygen atom, and rules out the opposite oxygen atom as a possible protonation site.     

Tautomerism in drug discovery

The influence of tautomerism on the precise structure of drugs and thus of their potential to interact with biological systems is discussed from thermodynamic and kinetic aspects. The types of tautomerism encountered in the structure of drugs in current use are surveyed together with the effect of pH, solvent polarity, and temperature.     

Tautomerism in Neutral Histidine

Histidine is an important natural amino acid, involved in many relevant biological processes, which, because of its physical properties, proved difficult to characterize experimentally in its neutral form. In this work, neutral histidine has been generated in the gas phase by laser ablation of solid samples and its N_εH tautomeric form unraveled through its rotational spectrum. The quadrupole hyperfine structure, arising from the existing three ¹⁴N nuclei, constituted a site‐specifically probe for revealing the tautomeric form as well as the side chain configuration of this proteogenic amino acid.     

Tautomerism in novel oxocorrologens

A novel corrole-type macrocycle, oxocorrologen (2), substituted with hemiquinone groups, has been synthesized. It was found to undergo multiple tautomerism of its exchangeable protons between electronegative atom sites at the macrocyclic core (nitrogen atoms) and periphery (phenol oxygen atoms). Alkylation at one macrocyclic nitrogen atom with a 4-nitrobenzyl group gave 3, which can exist in only two tautomeric forms depending on the solvent. Tautomerism has been studied by means of (1)H NMR spectroscopy in a variety of solvents and solvent mixtures. Tautomer structure assignments have been supported by DFT calculations of the relative energies of the tautomers. X-ray crystallography of the N-nitrobenzyl derivative has revealed that intramolecular hydrogen bonding may be responsible for stabilizing the observed tautomers. The solvent dependence of the tautomerism of 2 and 3 confers solvatochromism. Electrochemical measurements on 2 and 3 in their respective quinone forms have revealed irreversible processes, but indicate that they are both electron-deficient with a small HOMO-LUMO gap and first reduction potentials close to those of fullerene electron acceptors.     

An efficient similarity search based on indexing in large DNA databases

Index-based search algorithms are an important part of a genomic search, and how to construct indices is the key to an index-based search algorithm to compute similarities between two DNA sequences. In this paper, we propose an efficient query processing method that uses special transformations to construct an index. It uses small storage and it rapidly finds the similarity between two sequences in a DNA sequence database. At first, a sequence is partitioned into equal length windows. We select the likely subsequences by computing Hamming distance to query sequence. The algorithm then transforms the subsequences in each window into a multidimensional vector space by indexing the frequencies of the characters, including the positional information of the characters in the subsequences. The result of our experiments shows that the algorithm has faster run time than other heuristic algorithms based on index structure. Also, the algorithm is as accurate as those heuristic algorithms.     

Tautomerism in quinaldyl ketones

The quinaldyl ketone, 4-phenyl-3-(quinolin-2-yl)-butan-2-one was prepared by two methods: (a) benzylation of 1-(1H-quinolin-2-ylidene)propan-2-one in the presence of sodium hydride in dimethylformamide and (b) by the benzylative demethoxycarbonylation of methyl 2-(1H-quinolin-2-ylidene)-3-oxobutanoate in the presence of lithium bromide in hexamethylphosphoramide at 135°. In the absence of acid, the compound exists exclusively in the tautomeric form, 4-phenyl-3-(1H-quinolin-2-ylidene)butan-2-one.     

Phosphorotropic Tautomerism in Amidines

Abstract

We have discovered and systematically studied the fast reversible 1,3-rearrangements phosphorus-containing groups with tri-, tetra- and pentacoordinate phosphorus in amidines by means of NMR ¹H, ¹³C, ³¹p spectroscopy.     

Tautomerism in isomeric oxypurines

Starting with the assumption, based upon infrared spectroscopy evidence, that the oxypurines exist essentially in the keto form, calculations are performed by the CNDO/2 and the SCF MO CI methods in order to determine the most stable tautomers of these molecules with respect to the possible sites of attachement of the protons upon available ring nitrogens, and in order to evaluate their principal electronic properties. The calculations predict correctly the most stable tautomers, account satisfactorily for the observed ultraviolet absorption spectra and indicate that dipole moment measurements may be a particularly useful tool for the identification of the tautomers.

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Zusammenfassung Mit der von der UV-Spektroskopie gestützten Annahme, da\ die Oxypurine in der Keto-Form vorliegen, werden nach der CNDO/2-und der SCF MO CI-Methode die stabilsten tautomeren Formen dieser Moleküle bezüglich der möglichen Anlagerung von Protonen an die verfügbaren Stickstoffatome im Ring und ihre prinzipiellen elektronischen Eigenschaften berechnet. Die Rechnungen geben in übereinstimmung mit dem Experiment die stabilsten Tautomeren richtig wieder, zeigen eine gute übereinstimmung mit den UV-Absorptionsspektren und lassen darauf schlie\en, da\ das Dipolmoment eine zur Identifikation der Tautomeren geeignete Grö\e ist.

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Résumé Alors que la spectroscopie ultraviolette n'est pas capable d'indiquer sans ambiguité si les oxypurines existent préférentiellement sous la forme cétonique ou énolique, la spectroscopie infrarouge décide, elle, en faveur de la forme cétonique. Partant de cette constatation on effectue des calculs CNDO/2 et SCF MO CI pour déterminer les formes tautoméres les plus stables de différentes oxypurines par rapport aux sites de fixation de protons sur les azotes du cycle. Les calculs prédisent correctement dans chaque cas les tautoméres les plus probables, permettent de rendre compte de leurs spectres d'absorption et montrent l'utilité des mesures des moments dipolaires pour l'identification de ces tautoméres.

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This work was sponsored by the RCP No. 173 of the Centre National de la Recherche-Scientifique and grant No. 67-00-532 of the Délégation Générale à la Recherche Scientifique et Technique.     

Tautomerism in acyl tetronic acids

The tautomeric structures of some acetyl tetronic acids are studied by NMR analysis.     

PROLIX: rapid mining of protein-ligand interactions in large crystal structure databases

A central problem in structure-based drug design is understanding protein-ligand interactions quantitatively and qualitatively. Several recent studies have highlighted from a qualitative perspective the nature of these interactions and their utility in drug discovery. However, a common limitation is a lack of adequate tools to mine these interactions comprehensively, since exhaustive searches of the protein data bank are time-consuming and difficult to perform. Consequently, fundamental questions remain unanswered: How unique or how common are the protein-ligand interactions observed in a given drug design project when compared to all complexed structures in the protein data bank? Which interaction patterns might explain the affinity of a tool compound toward unwanted targets? To answer these questions and to enable the systematic and comprehensive study of protein-ligand interactions, we introduce PROLIX (Protein Ligand Interaction Explorer), a tool that uses sophisticated fingerprint representations of protein-ligand interaction patterns for rapid data mining in large crystal structure databases. Our implementation strategy pursues a branch-and-bound technique that enables mining against thousands of complexes within a few seconds. Key elements of PROLIX include (i) an intuitive interface that enables users to formulate complex queries easily, (ii) exceptional speed for results retrieval, and (iii) a sophisticated results summarization. Herein we describe the algorithms developed to enable complex queries and fast retrieval of search results, as well as the intuitive aspects of the user interface and summarization viewer.     

Tautomerism of rhodanine

Semiempirical (MINDO/3, AM1, PM3, MNDO) and ab initio (4-31G and 4-3IG + dAO/S basis sets) calculations on the relative stabilities and structures of the five potential tautomeric forms of rhodanine are reported. It is shown that all methods (excepting PM3) predict as most stable 2-thioxo-4-thiazolidinone. These results correspond to the known experimental data. The infrared spectrum of rhodanine was recorded for the region 4000-150 cm^–1, and the characteristic bands were compared with AM1 and 4-31G + dAO/S calculated frequencies. The transition states between five pairs of all possible tautomeric forms of the rhodanine were found by the AM1 method.