PubChem3D: a new resource for scientists

<p>Abstract</p> <p>Background</p> <p>PubChem is an open repository for small molecules and their experimental biological activity. PubChem integrates and provides search, retrieval, visualization, analysis, and programmatic access tools in an effort to maximize the utility of contributed information. There are many diverse chemical structures with similar biological efficacies against targets available in PubChem that are difficult to interrelate using traditional 2-D similarity methods. A new layer called PubChem3D is added to PubChem to assist in this analysis.</p> <p>Description</p> <p>PubChem generates a 3-D conformer model description for 92.3% of all records in the PubChem Compound database (when considering the parent compound of salts). Each of these conformer models is sampled to remove redundancy, guaranteeing a minimum (non-hydrogen atom pair-wise) RMSD between conformers. A diverse conformer ordering gives a maximal description of the conformational diversity of a molecule when only a subset of available conformers is used. A pre-computed search per compound record gives immediate access to a set of 3-D similar compounds (called "Similar Conformers") in PubChem and their respective superpositions. Systematic augmentation of PubChem resources to include a 3-D layer provides users with new capabilities to search, subset, visualize, analyze, and download data.</p> <p>A series of retrospective studies help to demonstrate important connections between chemical structures and their biological function that are not obvious using 2-D similarity but are readily apparent by 3-D similarity.</p> <p>Conclusions</p> <p>The addition of PubChem3D to the existing contents of PubChem is a considerable achievement, given the scope, scale, and the fact that the resource is publicly accessible and free. With the ability to uncover latent structure-activity relationships of chemical structures, while complementing 2-D similarity analysis approaches, PubChem3D represents a new resource for scientists to exploit when exploring the biological annotations in PubChem.</p

Hyperdimensional Analysis of Amino Acid Pair Distributions in Proteins

Our manuscript presents a novel approach to protein structure analyses. We have organized an 8-dimensional data cube with protein 3D-structural information from 8706 high-resolution non-redundant protein-chains with the aim of identifying packing rules at the amino acid pair level. The cube contains information about amino acid type, solvent accessibility, spatial and sequence distance, secondary structure and sequence length. We are able to pose structural queries to the data cube using program ProPack. The response is a 1, 2 or 3D graph. Whereas the response is of a statistical nature, the user can obtain an instant list of all PDB-structures where such pair is found. The user may select a particular structure, which is displayed highlighting the pair in question. The user may pose millions of different queries and for each one he will receive the answer in a few seconds. In order to demonstrate the capabilities of the data cube as well as the programs, we have selected well known structural features, disulphide bridges and salt bridges, where we illustrate how the queries are posed, and how answers are given. Motifs involving cysteines such as disulphide bridges, zinc-fingers and iron-sulfur clusters are clearly identified and differentiated. ProPack also reveals that whereas pairs of Lys residues virtually never appear in close spatial proximity, pairs of Arg are abundant and appear at close spatial distance, contrasting the belief that electrostatic repulsion would prevent this juxtaposition and that Arg-Lys is perceived as a conservative mutation. The presented programs can find and visualize novel packing preferences in proteins structures allowing the user to unravel correlations between pairs of amino acids. The new tools allow the user to view statistical information and visualize instantly the structures that underpin the statistical information, which is far from trivial with most other SW tools for protein structure analysis

Continuum solvent model studies of the interactions of an anticonvulsant drug with a lipid bilayer.

Valproic acid (VPA) is a short, branched fatty acid with broad-spectrum anticonvulsant activity. It has been suggested that VPA acts directly on the plasma membrane. We calculated the free energy of interaction of VPA with a model lipid bilayer using simulated annealing and the continuum solvent model. Our calculations indicate that VPA is likely to partition into the bilayer both in its neutral and charged forms, as expected from such an amphipathic molecule. The calculations also show that VPA may migrate (flip-flop) across the membrane; according to our (theoretical) study, the most likely flip-flop path at neutral pH involves protonation of VPA pending its insertion into the lipid bilayer and deprotonation upon departure from the other side of the bilayer. Recently, the flip-flop of long fatty acids across lipid bilayers was studied using fluorescence and NMR spectroscopies. However, the measured value of the flip-flop rate appears to depend on the method used in these studies. Our calculated value of the flip-flop rate constant, 20/s, agrees with some of these studies. The limitations of the model and the implications of the study for VPA and other fatty acids are discussed

Consensus Models of Activity Landscapes with Multiple Chemical, Conformer, and Property Representations

We report consensus Structure–Activity Similarity (SAS) maps that address the dependence of activity landscapes on molecular representation. As a case study, we characterized the activity landscape of 54 compounds with activities against human cathepsin B (hCatB), human cathepsin L (hCatL), and Trypanosoma brucei cathepsin B (TbCatB). Starting from an initial set of 28 descriptors we selected ten representations that capture different aspects of the chemical structures. These included four 2D (MACCS keys, GpiDAPH3, pairwise, and radial fingerprints) and six 3D (4p and piDAPH4 fingerprints with each including three conformers) representations. Multiple conformers are used for the first time in consensus activity landscape modeling. The results emphasize the feasibility of identifying consensus data points that are consistently formed in different reference spaces generated with several fingerprint models, including multiple 3D conformers. Consensus data points are not meant to eliminate data, disregarding, for example, “true” activity cliffs that are not identified by some molecular representations. Instead, consensus models are designed to prioritize the SAR analysis of activity cliffs and other consistent regions in the activity landscape that are captured by several molecular representations. Systematic description of the SARs of two targets give rise to the identification of pairs of compounds located in the same region of the activity landscape of hCatL and TbCatB suggesting similar mechanisms of action for the pairs involved. We also explored the relationship between property similarity and activity similarity and found that property similarities are suitable to characterize SARs. We also introduce the concept of structure–property-activity (SPA) similarity in SAR studies

Circular dichroism and ultraviolet resonance raman indicate little Arg-Glu side chain α-helix peptide stabilization

Electrostatic interactions between side chains can control the conformation and folding of peptides and proteins. We used circular dichroism (CD) and ultraviolet (UV) resonance Raman spectroscopy (UVRR) to examine the impact of side chain charge on the conformations of two 21 residue mainly polyala peptides with a few Arg and Glu residues. We expected that attractions between Arg-10 and Glu-14 side chains would stabilize the α-helix conformation compared to a peptide with an Arg-14. Surprisingly, CD suggests that the peptide with the Glu-14 is less helical. In contrast, the UVRR show that these two peptides have similar α-helix content. We conclude that the peptide with Glu-14 has the same net α-helix content as the peptide with the Arg but has two α-helices of shorter length. Thus, side chain interactions between Arg-10 and Glu-14 have a minor impact on α-helix stability. The thermal melting of these two peptides is similar. However the Glu-14 peptide pH induced melting forms type III turn structures that form α-helix-turn-α-helix conformations. © 2011 American Chemical Society