Empirical scale of side-chain conformational entropy in protein folding.

A major effect in the energetics of protein folding is the loss of conformational entropy of the side-chains. The definition of entropy as the Boltzmann sampling over all states (S = -R sigma p(i) ln p(i)) requires evaluation of the probability (p(i)) of the system being in rotameric state i. The principle of this paper is to obtain an estimate of p(i) from the observed distribution of exposed side-chain rotamers in 50 non-homologous protein crystal structures. However because of limited data we show that for all side-chains except Asn, Asp and Glu the side-chain distribution is independent of burial and accordingly all data were pooled in the calculation of p(i). For Asn, Asp and Glu side-chains with relative accessibility > 60% were used. The scale includes effects due to the symmetry of side-chains such as Phe and the free rotation of side-chain amide, carboxyl and hydroxyl groups. An empirical scale for the loss of side-chain conformational entropy during protein folding is thereby obtained. Values of the change in free energy due to entropy (-T delta S) on burying a side-chain range from 0 for Ala, Gly and Pro to +2.1 kcal/mol for Gln (T = 300 K). We explore the consistency of a simple model for protein folding that includes side-chain entropy, main-chain entropy, hydrophobicity and hydrogen bonding. The stability of site-directed mutations is discussed in terms of conformational entropy.

Evaluation of the sequence template method for protein structure prediction. Discrimination of the (beta/alpha)8-barrel fold.

A multiple alignment of five (beta/alpha)8-barrel enzymes has been derived from their structure. The eight beta-strands and eight alpha-helices of the (beta/alpha)8-barrel are correctly aligned and the equivalenced residues in these regions fulfil similar structural roles. Each beta-strand has a central core of usually four residues, two residues contribute side-chains to the barrel core and the other two residues are involved in beta-strand/alpha-helix contacts. However, the fold imposes no constraints on the volumes of the residues at either a local or global level: the volume of the beta-barrel core varies between 1088 A3 in glycolate oxidase and 1571 A3 in taka-amylase. Sequence motifs derived from the multiple alignment were scanned against a database of 124 protein sequences, including 17 (beta/alpha)8-barrel enzymes. The results were evaluated in terms of the discrimination of (beta/alpha)8-barrel sequences and the quality of the alignments obtained. One motif was able to identify the top 12% of high scoring sequences as forming (beta/alpha)8-barrels with 50% accuracy and the bottom 50% of sequences as not being (beta/alpha)8-barrel proteins with 100% accuracy. However, in most instances the alignments were poor. The reasons for this are discussed with reference to the (beta/alpha)8-barrel proteins and the sequence motif method in general.

Methods for library design and optimisation.

The introduction of combinatorial chemistry groups into pharmaceutical companies provoked a desire for efficient and effective methods for library design and optimisation. This, in turn, has resulted in a large number of scientific publications, detailing a variety of approaches to the problem. This review attempts to describe the major works in the literature, to set them in context both chronologically and scientifically, and to identify the outstanding challenges that must be addressed, if this area of research is to maintain the rapid progress seen hitherto.

Design of a compound screening collection for use in high throughput screening.

In this paper we introduce a quantitative model that relates chemical structural similarity to biological activity, and in particular to the activity of lead series of compounds in high-throughput assays. From this model we derive the optimal screening collection make up for a given fixed size of screening collection, and identify the conditions under which a diverse collection of compounds or a collection focusing on particular regions of chemical space are appropriate strategies. We derive from the model a diversity function that may be used to assess compounds for acquisition or libraries for combinatorial synthesis by their ability to complement an existing screening collection. The diversity function is linked directly through the model to the goal of more frequent discovery of lead series from high-throughput screening. We show how the model may also be used to derive relationships between collection size and probabilities of lead discovery in high-throughput screening, and to guide the judicious application of structural filters.

Classification of kinase inhibitors using BCUT descriptors.

BCUTs are an interesting class of molecular descriptor which have been proposed for a number of design and QSAR type tasks. It is important to understand what kind of information any particular descriptor encodes and to be able to relate this to the biological properties of the molecules. In this paper we present studies with BCUTs for the classification of ATP site directed kinase inhibitors active against five different protein kinases: three from the serine/threonine family and two from the tyrosine kinase family. In combination with a chemometric method, PLS discriminant analysis, the BCUTs are able to correctly classify the ligands according to their target. A novel class of kinase inhibitors is correctly predicted as inhibitors of the EGFR tyrosine kinase. Comparison with other descriptor types such as two-dimensional fingerprints and three-dimensional pharmacophore-based descriptors allows us to gain an insight into the level of information contained within the BCUTs.

The reduced graph descriptor in virtual screening and data-driven clustering of high-throughput screening data.

Virtual screening and high-throughput screening are two major components of lead discovery within the pharmaceutical industry. In this paper we describe improvements to previously published methods for similarity searching with reduced graphs, with a particular focus on ligand-based virtual screening, and describe a novel use of reduced graphs in the clustering of high-throughput screening data. Literature methods for reduced graph similarity searching encode the reduced graphs as binary fingerprints, which has a number of issues. In this paper we extend the definition of the reduced graph to include positively and negatively ionizable groups and introduce a new method for measuring the similarity of reduced graphs based on a weighted edit distance. Moving beyond simple similarity searching, we show how more flexible queries can be built using reduced graphs and describe a database system that allows iterative querying with multiple representations. Reduced graphs capture many important features of ligand-receptor interactions and, in conjunction with other whole molecule descriptors, provide an informative way to review HTS data. We describe a novel use of reduced graphs in this context, introducing a method we have termed data-driven clustering, that identifies clusters of molecules represented by a particular whole molecule descriptor and enriched in active compounds.

DIVSEL and COMPLIB--strategies for the design and comparison of combinatorial libraries using pharmacophoric descriptors.

Screening synthetic combinatorial libraries may facilitate rapid drug lead discovery by substantially increasing the number of molecules tested. Drug discovery efficiency and productivity can be further improved by designing libraries to maximize their molecular diversity or by comparing them to existing collections of compounds and/or libraries to select those that complement the properties already well represented. In this paper we describe two strategies to aid in the design and comparison of combinatorial libraries. The methods employ multi-pharmacophore three-dimensional (3D) descriptors in combination with two recent proposals for dissimilarity-based compound selection and library comparison. This method allows the design to be performed in product space and library comparison to consider all pair-wise intermolecular contributions to the diversity.