Using the gini coefficient to measure the chemical diversity of small-molecule libraries.

Modern databases of small organic molecules contain tens of millions of structures. The size of theoretically available chemistry is even larger. However, despite the large amount of chemical information, the "big data" moment for chemistry has not yet provided the corresponding payoff of cheaper computer-predicted medicine or robust machine-learning models for the determination of efficacy and toxicity. Here, we present a study of the diversity of chemical datasets using a measure that is commonly used in socioeconomic studies. We demonstrate the use of this diversity measure on several datasets that were constructed to contain various congeneric subsets of molecules as well as randomly selected molecules. We also apply our method to a number of well-known databases that are frequently used for structure-activity relationship modeling. Our results show the poor diversity of the common sources of potential lead compounds compared to actual known drugs. © 2016 Wiley Periodicals, Inc.

Development and implementation of (Q)SAR modeling within the CHARMMing web-user interface.

Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (www.charmming.org). This new module implements some of the most recent advances in modern machine learning algorithms-Random Forest, Support Vector Machine, Stochastic Gradient Descent, Gradient Tree Boosting, so forth. A user can import training data from Pubchem Bioassay data collections directly from our interface or upload his or her own SD files which contain structures and activity information to create new models (either categorical or numerical). A user can then track the model generation process and run models on new data to predict activity.

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods.

Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ≤0.95 µM. We applied our SAR models to various drug-like databases and identified novel chemical scaffolds for NS5B inhibitors. Subsequent in vitro antiviral assays suggested a new activity for an existing prodrug, Candesartan cilexetil, which is currently used to treat hypertension and heart failure but has not been previously tested for anti-HCV activity. We also identified NS5B inhibitors with two novel non-nucleoside chemical motifs.

Computational tools and resources for metabolism-related property predictions. 2. Application to prediction of half-life time in human liver microsomes.

BACKGROUND: The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes. METHOD: A variety of QSAR models generated using different statistical methods and descriptor sets implemented in both open-source and commercial programs (KNIME, GUSAR and StarDrop) were analyzed. The models obtained were compared using four different external validation sets from public and commercial data sources, including two smaller sets of in vivo half-life data in humans. CONCLUSION: In many cases, the accuracy of prediction achieved on one external test set did not correspond to the results achieved with another test set. The most predictive models were used for predicting the metabolic stability of compounds from the open NCI database, the results of which are publicly available on the NCI/CADD Group web server ( http://cactus.nci.nih.gov ).

PDB ligand conformational energies calculated quantum-mechanically.

We present here a greatly updated version of an earlier study on the conformational energies of protein-ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med. Chem. 1995, 3, 411-428], with the goal of improving on all possible aspects such as number and selection of ligand instances, energy calculations performed, and additional analyses conducted. Starting from about 357,000 ligand instances deposited in the 2008 version of the Ligand Expo database of the experimental 3D coordinates of all small-molecule instances in the PDB, we created a "high-quality" subset of ligand instances by various filtering steps including application of crystallographic quality criteria and structural unambiguousness. Submission of 640 Gaussian 03 jobs yielded a set of about 415 successfully concluded runs. We used a stepwise optimization of internal degrees of freedom at the DFT level of theory with the B3LYP/6-31G(d) basis set and a single-point energy calculation at B3LYP/6-311++G(3df,2p) after each round of (partial) optimization to separate energy changes due to bond length stretches vs bond angle changes vs torsion changes. Even for the most "conservative" choice of all the possible conformational energies-the energy difference between the conformation in which all internal degrees of freedom except torsions have been optimized and the fully optimized conformer-significant energy values were found. The range of 0 to ~25 kcal/mol was populated quite evenly and independently of the crystallographic resolution. A smaller number of "outliers" of yet higher energies were seen only at resolutions above 1.3 Å. The energies showed some correlation with molecular size and flexibility but not with crystallographic quality metrics such as the Cruickshank diffraction-component precision index (DPI) and R(free)-R, or with the ligand instance-specific metrics such as occupancy-weighted B-factor (OWAB), real-space R factor (RSR), and real-space correlation coefficient (RSCC). We repeated these calculations with the solvent model IEFPCM, which yielded energy differences that were generally somewhat lower than the corresponding vacuum results but did not produce a qualitatively different picture. Torsional sampling around the crystal conformation at the molecular mechanics level using the MMFF94s force field typically led to an increase in energy.

Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk five years on.

BACKGROUND: The Blue Obelisk movement was established in 2005 as a response to the lack of Open Data, Open Standards and Open Source (ODOSOS) in chemistry. It aims to make it easier to carry out chemistry research by promoting interoperability between chemistry software, encouraging cooperation between Open Source developers, and developing community resources and Open Standards. RESULTS: This contribution looks back on the work carried out by the Blue Obelisk in the past 5 years and surveys progress and remaining challenges in the areas of Open Data, Open Standards, and Open Source in chemistry. CONCLUSIONS: We show that the Blue Obelisk has been very successful in bringing together researchers and developers with common interests in ODOSOS, leading to development of many useful resources freely available to the chemistry community.

Using conformationally locked nucleosides to calibrate the anomeric effect: Implications for glycosyl bond stability.

Steric and electronic parameters such as the anomeric effect (AE) and gauche effect play significant roles in steering the North ⇆ South equilibrium of nucleosides in solution. Two isomeric oxa-bicyclo[3.1.0]hexane nucleosides that are conformationally locked in either the North or the South conformation of the pseudorotational cycle were designed to study the consequences of having the AE operational or not, independent of other parameters. The rigidity of the system allowed the orientation of the orbitals involved to be set in "fixed" relationships, either antiperiplanar where the AE is permanently "on", or gauche where the AE is impaired. The consequences of these two alternatives were subject to high-level calculations and measured experimentally by x-ray crystallography, hydrolytic stability of the glycosyl bond, and pKa values.

Optical structure recognition software to recover chemical information: OSRA, an open source solution.

Until recently most scientific and patent documents dealing with chemistry have described molecular structures either with systematic names or with graphical images of Kekulé structures. The latter method poses inherent problems in the automated processing that is needed when the number of documents ranges in the hundreds of thousands or even millions since graphical representations cannot be directly interpreted by a computer. To recover this structural information, which is otherwise all but lost, we have built an optical structure recognition application based on modern advances in image processing implemented in open source tools, OSRA. OSRA can read documents in over 90 graphical formats including GIF, JPEG, PNG, TIFF, PDF, and PS, automatically recognizes and extracts the graphical information representing chemical structures in such documents, and generates the SMILES or SD representation of the encountered molecular structure images.

What are the consequences of freezing the anomeric effect in nucleosides?

The consequences of freezing the orientation of the oxygen's lone pair orbitals--which determines whether the anomeric effect is operative or not--were studied theoretically and experimentally in two oxobicyclo-[3.1.0]hexane nucleosides (1 and 2). The results showed significant differences in the properties of these molecules, which correlated with the magnitude of the n2 --> sigma * delocalization.

Dynamics of infraslow potentials in the primary auditory cortex: component analysis and contribution of specific thalamic-cortical and non-specific brainstem-cortical influences.

Several available reports demonstrate the presence of infraslow activity (<0.5 Hz) in structures of the auditory system of the brain. It was reported earlier that specific alterations of this activity in the domain of seconds (0.1-0.5 Hz) occurred in the medial geniculate nucleus (MGN) and primary auditory cortex (A1) in response to acoustic stimuli. The present study was performed to test two hypotheses: (1) that potentials in the domain of seconds (0.1-0.5 Hz) reflect specific and direct interactions of the MGN and A1 during neural processing of sensory information, and (2) that low-frequency infraslow potentials in the A1 (<0.1 Hz) are related to brainstem influences originating from the locus coeruleus (LC) and dorsal raphe nucleus (DRN). The experimental subjects were 25 adult rats with chronic stereotaxic electrodes implanted in the MGN, A1, LC, and DRN. The animals were anesthetized and infraslow activity was once recorded under several experimental conditions: (1) in the A1 before and after electrical stimulation of MGN, (2) in the A1 before and after electrical stimulation of LC, and (3) in the A1 before and after electrical stimulation of DRN. The effects of MGN stimulation were limited to overall increases in spectral power in the frequency domain of 0.1-0.5 Hz. Specifically, power increased in the frequencies of 0.1-0.25, 0.35-0.4, and 0.45-0.5 Hz in the A1 after MGN stimulation. The electrical stimulation of either the LC or DRN affected only multisecond activity (0.0167-0.04 Hz) in the A1 in the similar way (increase of powers of multisecond potentials), but it does not induced any changes in the activity with the frequencies of 0.1-0.5 Hz in this structure. These results support tentative conclusions that infraslow activity in the range of 0.1-0.5 Hz is implicated in specific mechanisms of interactions within the MGN-A1 thalamic-cortical system, whereas multisecond potentials (0.0167-0.04 Hz) in A1 are mainly attributed to the influences of brainstem nuclei (like LC and DRN) on general neuronal excitability of this auditory cortical area.

Sound-induced changes of infraslow brain potential fluctuations in the medial geniculate nucleus and primary auditory cortex in anaesthetized rats.

Recent publications indicate the presence of infraslow activity (<0.5 Hz) in subcortical and cortical sites of the auditory system of the brain. It has been reported that this activity might be sensitive to acoustic stimuli. Yet the dynamics of infraslow brain potential (ISBP) fluctuations in these structures and their potential sensitivity to auditory stimuli are unknown. The present study was performed in order to test the hypothesis that extracellular ISBP activity in the medial geniculate nucleus (MGN) and the primary auditory cortex (A1) responds concurrently to acoustic stimuli. The experimental subjects were 5 adult rats with chronic stereotaxic electrodes implanted in MGN and A1. The animals were anesthetized and recordings were made in both sites during both silence and rhythmical acoustic stimulation. Our results support the hypothesis that these fluctuations are sensitive to acoustic stimuli. There were similar changes in ISBP activity in the MGN and A1 in response to rhythmic acoustic stimulation. Specifically, there were significant increases in the frequency range of seconds. Based on these findings, we suggest that sound-correlated changes in infraslow activity in the range of seconds in the MGN and A1 reflect specific mechanisms of neural processing of acoustic information in the auditory system of the brain.

Very slow brain potential fluctuations (< 0.5 Hz) in visual thalamus and striate cortex after their successive electrical stimulation in lightly anesthetized rats.

Recently accumulating evidence demonstrates the presence of very slow activity (< 0.5 Hz) in structures of the visual system of the brain. It was found in our laboratory earlier that specific and significant alterations of this activity (mainly in the domain of seconds) occurred in the visual system in response to illumination changes. The present study was performed in order to test the hypothesis that potentials in the domain of seconds reflect specific and direct interactions of the lateral geniculate nucleus (LGN) and the primary visual cortex (V1) during neural processing of sensory information. The experimental subjects were seven adult rats with chronic stereotaxic electrodes implanted in the LGN and V1. Animals were lightly anesthetized and the recordings were made in the LGN before and after electrical stimulation of V1 and also in the V1 before and after stimulation of LGN. The main findings were significant spectral changes in the domain of seconds in the V1 after LGN electrical stimulation and similar changes in the LGN after V1 electrical stimulation. These changes were manifested as significant increases in power in the domain of seconds (0.1-0.5 Hz). Significant responses were detected in the both LGN and V1 multisecond activities (pre- vs. post-stimulus recordings). The changes were opposite in direction in the LGN and V1. The obtained results support the conclusion that very slow activity in the domain of seconds reflects specific mechanisms of forward and backward interactions within the LGN-V1 thalamic-cortical-thalamic system, while multisecond activity relates to global neuronal activity fluctuations.

Very slow potentials in the lateral geniculate complex and primary visual cortex during different illumination changes in freely moving rats.

Previous literature has shown different forms of very slow oscillatory phenomena (0-0.5 Hz) in the structures of brain visual system. It was demonstrated in aforementioned publications that this infraslow activity might be sensitive to the level of environmental illumination. This study was performed to test the hypothesis that extracellular very slow brain potential (VSBP) oscillations or fluctuations in lateral geniculate complex (LGC) and primary visual cortex (PVC) are responding specifically and concurrently to different illumination changes. Experiments were conducted on five albino rats with chronically implanted stereotaxic electrodes in LGC and PVC brain sites. Our results support the aforementioned suggestion and revealed significant and similar patterns of VSBP modification within a frequency domain of seconds (0.1-0.25 Hz) in both the LGC and PVC in response to darkness, illumination and photostimulation. It is also documented here that significant and similar changes of multisecond activity (0.02-0.04 Hz) occur in both investigated brain sites in response to photostimulation only. Based on these findings, we propose that a possible role for VSBP oscillations in the LGC and PVC should be strongly considered in the CNS mechanisms of visual information processing.

PROSIT: pseudo-rotational online service and interactive tool, applied to a conformational survey of nucleosides and nucleotides.

A Pseudo-Rotational Online Service and Interactive Tool (PROSIT) designed to perform complete pseudorotational analysis of nucleosides and nucleotides is described. This service is freely available at http://cactus.nci.nih.gov/prosit/. Files containing nucleosides/nucleotides or DNA/RNA segments, isolated or bound to other molecules (e.g., a protein) can be uploaded to be processed by PROSIT. The service outputs the pseudorotational phase angle P, puckering amplitude numax, and other related information for each nucleoside/nucleotide detected. The service was implemented using the chemoinformatics toolkit CACTVS. PROSIT was used for a survey of nucleosides contained in the Cambridge Structural Database and nucleotides in high-resolution crystal structures from the Nucleic Acid Database. Special cases discussed include nucleosides having constrained sugar moieties with extreme puckering amplitudes, and several specific DNA/RNA helices and protein-bound DNA oligonucleotides (Dickerson-Drew dodecamer, RNA/DNA hybrid viral polypurine tract, Z-DNA enantiomers, B-DNA containing (L)-alpha-threofuranosyl nucleotides, TATA-box binding protein/TATA-box complex, and DNA (cytosine C5)-methyltransferase complexed with an oligodeoxyribonucleotide containing transition state analogue 5,6-dihydro-5-azacytosine). When the puckering amplitude decreases to a small value, the sugar becomes increasingly planar, thus reducing the significance of the phase angle P. We introduce the term "central conformation" to describe this part of the pseudorotational hyperspace in contrast to the conventional north and south conformations.

Very slow potential oscillations in locus coeruleus and dorsal raphe nucleus under different illumination in freely moving rats.

Recent findings have revealed very slow (<0.5 Hz) oscillatory phenomena in the structures of the brain visual system. It has been proposed that very slow brain potentials in an extremely slow domain, less than 0.1 Hz, recorded from the lateral geniculate complex and primary visual cortex are associated with periodic influences originating from the locus coeruleus and dorsal raphe nucleus. The present study was performed to test the hypothesis that extremely slow brain potential oscillatory patterns in the locus coeruleus and dorsal raphe nucleus during several types of visual stimulation--light exposure, darkness, and photostimulation--are similar to those in the primary visual cortex and lateral geniculate complex under the same conditions of illumination. The results support this hypothesis. Specifically, spectral patterns of multisecond oscillations in the range of 0.02-0.04 Hz and fluctuations in the domain of minutes (below 0.002 Hz) were present in both the locus coeruleus and dorsal raphe nucleus and were similar to those found in the primary visual cortex and lateral geniculate complex. Additionally, we detected significant increases in the power spectra of multisecond oscillations in both nuclei in response to photostimulation (P<0.05). Our tentative conclusion is that extremely slow potentials in the locus coeruleus and dorsal raphe nucleus contribute to the regulation of extremely slow activity in the brain visual system.