Pharmacophore Binding Motifs for Nicotinamide Adenine Dinucleotide Analogues Across Multiple Protein Families: A Detailed Contact-Based Analysis of the Interaction between Proteins and NAD(P) Cofactors

We have analyzed the protein-binding pharmacophore of NAD and its close analogues in all protein–ligand structures available in the RCSB database as of February 2012; this analysis has then been used to assess the novelty of structures emerging after that date. We show that proteins have evolved diverse pharmacophore motifs for binding the adenine moiety, fewer, but still diverse, motifs for nicotinamide, and a very limited set of motifs for binding the pyrophosphate linker. Our exhaustive analysis includes a pharmacophore contact analysis for over 1900 protein–ligand structures containing NAD analogues; we have benchmarked this set of contacts against nearly 27 000 protein–ligand structures to demonstrate that the diversity of interactions seen with NAD is very similar to that seen for all other ligands. Hence, variation in binding motifs for NAD is not distinct from that observed for other ligands and they show significant variation across protein families

Mining the Cambridge Structural Database for Matched Molecular Crystal Structures: A Systematic Exploration of Isostructurality

The Cambridge Structural Database (CSD) is the world leading collection of small-molecule crystal structures and represents an invaluable resource for crystal engineers. It enables structures to be readily compared and new insights to be gained from the comparison. In order to search the database for pairs of structures that are related by the same chemical transformation, and to systematically investigate the effect of this transformation on crystal packing, a repository of matched molecular crystal structures has been derived from the CSD. This makes it easy to find all pairs of structures differing by the same chemical change or, alternatively, all available chemical modifications to a given CSD entry. Our analysis shows one of the many possible applications of these data. An extensive, yet not exhaustive, exploration of isostructurality across the entire CSD has been carried out with the aim of identifying packing features within crystals that maintain isostructurality. With particular focus on terminal chemical modifications observed between single-component structures with <i>Z</i>′ equal to 1, packing similarity has been calculated with an enhanced version of existing software. Across the entire data set of approximately 125 000 matched molecular pairs, 4% of the pairs were isostructural. Several cases showed an enrichment with respect to this baseline value, and examples have been discussed to illustrate some of the questions which can be asked and how they can be answered using the data set. This will open up avenues of research for the future and increase our understanding of the impact of functional groups on crystal packing

An Extensive and Diverse Set of Molecular Overlays for the Validation of Pharmacophore Programs

The pharmacophore hypothesis plays a central role in both the design and optimization of drug-like ligands. Pharmacophore patterns are invoked to explain the binding affinity of ligands and to enable the design of chemically distinct scaffolds that show affinity for a protein target of interest. The importance of pharmacophores in rationalizing ligand affinity has led to numerous algorithms that seek to overlay ligands based on their pharmacophoric features. All such algorithms must be validated with respect to known ligand overlays, usually by extracting ligand overlay sets from the Protein Data Bank (PDB). This validation step creates the problem of which of the known overlays to select and from which proteins. The large number of structures and protein families in the PDB makes it difficult to establish a definitive overlay set; as a result, validation studies have rarely employed the same data sets. We have therefore undertaken an exhaustive analysis of the RCSB PDB to identify 121 distinct ligand overlay sets. We have defined a robust protein overlay protocol, which is free from subjective interpretation over which residues to include, and we have analyzed each overlay set on the basis of whether they provide evidence for the pharmacophore hypothesis. Our final data set spans a broad range of structural types and degrees of difficulty and includes overlays that any algorithm should be able to reproduce, as well as some for which there is very weak evidence for a conserved pharmacophore at all. We provide this set in the hope that it will prove definitive, at least until the PDB is greatly enriched with further structures or with radically different protein folds and families. Upon publication, the data set will be available for free download from the Web site of the Cambridge Crystallographic Data Centre

Protein–Ligand Informatics Force Field (PLIff): Toward a Fully Knowledge Driven “Force Field” for Biomolecular Interactions

The Protein Data Bank (PDB) contains a wealth of data on nonbonded biomolecular interactions. If this information could be distilled down to nonbonded interaction potentials, these would have some key advantages over standard force fields. However, there are some important outstanding issues to address in order to do this successfully. This paper introduces the protein–ligand informatics “force field”, PLIff, which begins to address these key challenges (https://bitbucket.org/AstexUK/pli). As a result of their knowledge-based nature, the next-generation nonbonded potentials that make up PLIff automatically capture a wide range of interaction types, including special interactions that are often poorly described by standard force fields. We illustrate how PLIff may be used in structure-based design applications, including interaction fields, fragment mapping, and protein–ligand docking. PLIff performs at least as well as state-of-the art scoring functions in terms of pose predictions and ranking compounds in a virtual screening context

Assessment of a Cambridge Structural Database-Driven Overlay Program

We recently published an improved methodology for overlaying multiple flexible ligands and an extensive data set for validating pharmacophore programs. Here, we combine these two developments and present evidence of the effectiveness of the new overlay methodology at predicting correct superimpositions for systems with varying levels of complexity. The overlay program was able to generate correct predictions for 95%, 73%, and 39% of systems classified as easy, moderate, and hard, respectively

Biological data of alloxan-based compounds 1–9.

<p>We report the pIC₅₀ or % of inhibition at 100 µM.</p

Thermodynamic integration for the case BAR to BCL.

<p>The plot shows the dV/dλ curves assembled from 13 lambda points. Transformations in water are represented as well as those in the protein for the three simulation steps.</p

Thermodynamic cycle. Events A and B represent the binding of two different ligands to a protein, events C and D indicate the conversion from one ligand to the other in the bound and hydrated states, respectively.

<p>The free energy differences between the processes A and C can be obtained calculating the free energy differences between B and D.</p

GOLD fitness values for top-scored docking solutions.

<p>GOLD fitness values for top-scored docking solutions.</p

Interactions of BAM with the binding pocket.

<p>The final snapshot of the 5 ns MD trajectory is rendered in white capped stick models. Fitting spheres represent the positions visited during the 5 ns MD by the guanidine carbon atom of Arg149, colored in cyan, and by the oxygen backbone atom of Leu116, colored in red, of MMP-2 (PDB code 1HOV). Black dashed lines show the coordination to the catalytic zinc ion.</p