PubMed Health⌕ Search

Biomedical subjects

Peter Willett

Publications and source records attributed to Peter Willett.

At least 19 recordsLinked to original sources
PubMed2007

Evaluation of machine-learning methods for ligand-based virtual screening.

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed.

Artificial Intelligence↗
PubMed2006

Similarity-based virtual screening using 2D fingerprints.

This paper summarizes recent work at the University of Sheffield on virtual screening methods that use 2D fingerprint measures of structural similarity. A detailed comparison of a large number of similarity coefficients demonstrates that the well-known Tanimoto coefficient remains the method of choice for the computation of fingerprint-based similarity, despite possessing some inherent biases related to the sizes of the molecules that are being sought. Group fusion involves combining the results of similarity searches based on multiple reference structures and a single similarity measure. We demonstrate the effectiveness of this approach to screening, and also describe an approximate form of group fusion, turbo similarity searching, that can be used when just a single reference structure is available.

Chemistry, Pharmaceutical↗
PubMed2006

GALAHAD: 1. pharmacophore identification by hypermolecular alignment of ligands in 3D.

Alignment of multiple ligands based on shared pharmacophoric and pharmacosteric features is a long-recognized challenge in drug discovery and development. This is particularly true when the spatial overlap between structures is incomplete, in which case no good template molecule is likely to exist. Pair-wise rigid ligand alignment based on linear assignment (the LAMDA algorithm) has the potential to address this problem (Richmond et al. in J Mol Graph Model 23:199-209, 2004). Here we present the version of LAMDA embodied in the GALAHAD program, which carries out multi-way alignments by iterative construction of hypermolecules that retain the aggregate as well as the individual attributes of the ligands. We have also generalized the cost function from being purely atom-based to being one that operates on ionic, hydrogen bonding, hydrophobic and steric features. Finally, we have added the ability to generate useful partial-match 3D search queries from the hypermolecules obtained. By running frozen conformations through the GALAHAD program, one can utilize the extended version of LAMDA to generate pharmacophores and pharmacosteres that agree well with crystal structure alignments for a range of literature datasets, with minor adjustments of the default parameters generating even better models. Allowing for inclusion of partial match constraints in the queries yields pharmacophores that are consistently a superset of full-match pharmacophores identified in previous analyses, with the additional features representing points of potentially beneficial interaction with the target.

Algorithms↗
PubMed2006

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data.

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure.

Crystallography, X-Ray↗
PubMed2005

Enhancing the effectiveness of similarity-based virtual screening using nearest-neighbor information.

We test the hypothesis that fusing the outputs of similarity searches based on a single bioactive reference structure and on its nearest neighbors (of unknown activity) is more effective (in terms of numbers of high-ranked active structures) than a similarity search involving just the reference structure. This turbo similarity searching approach provides a simple way to enhance the effectiveness of simulated virtual screening searches of the MDL Drug Data Report database.

Computing Methodologies↗
PubMed2005

Use of graph theory to identify patterns of deprivation and high morbidity and mortality in public health data sets.

OBJECTIVE: An important part of public health is identifying patterns of poor health and deprivation. Specific patterns of poor health may be associated with features of the geographic environment where contamination or pollution may be occurring. For example, there may be clusters of poor health surrounding nuclear power stations, whereas major roads or rivers may be associated with areas of poor health alongside the feature in chains. Current methods are limited in their capacity to search for complex patterns in geographic data sets. The objective of this study was to determine whether graph theory could be used to identify patterns of geographic areas that have high levels of deprivation, morbidity, and mortality in a public health database. The geographic areas used in the study were enumeration districts (EDs), which are the lowest level of census geography in England and Wales, representing on average 200 households in the 1991 census. More specifically, the study aimed to identify chains of EDs with high deprivation, morbidity, and mortality that might be adjacent to specific types of geographic features, i.e., rivers or major roads. DESIGN: The maximum common subgraph (MCS) algorithm was used to search for seven query patterns of deprivation and poor health within the Trent region. Query pattern 1 represented a linear chain of five EDs and query patterns 2 to 7 represented the possible clusters of the five EDs. To identify chains of EDs with high deprivation, morbidity, and mortality, the results from the query patterns 2 to 7 were used to remove patterns (option 1) and EDs (option 2) from the results of query pattern 1. MEASUREMENTS: Data on the Townsend Material Deprivation Index, standardized long-term limiting illness and standardized all-cause mortality rates were used for the 10,665 EDs within the Trent region. RESULTS: The MCS algorithm retrieved a range of patterns and EDs from the database for the queries. Query pattern 1 identified 3,838 patterns containing a total of 195 EDs. When the patterns retrieved using query patterns 2 to 7 were removed from the 3,838 patterns using option 1, 1,704 patterns remained containing 161 EDs. When the EDs retrieved using query patterns 2 to 7 were removed from the 195 EDs identified by query pattern 1 using option 2, 12 EDs remained. The MCS algorithm was therefore able to reduce the numbers of patterns and EDs to allow manual examination for chains of EDs and for that which might be associated with them. CONCLUSION: The study demonstrates the potential of the MCS algorithm for searching for specific patterns of need. This method has potential for identifying such patterns in relation to local geographic features for public health.

Algorithms↗
PubMed2004

A structural similarity analysis of double-helical DNA.

A database of the structural properties of all 32,896 unique DNA octamer sequences has been calculated, including information on stability, the minimum energy conformation and flexibility. The contents of the database have been analysed using a variety of Euclidean distance similarity measures. A global comparison of sequence similarity with structural similarity shows that the structural properties of DNA are much less diverse than the sequences, and that DNA sequence space is larger and more diverse than DNA structure space. Thus, there are many very different sequences that have very similar structural properties, and this may be useful for identifying DNA motifs that have similar functional properties that are not apparent from the sequences. On the other hand, there are also small numbers of almost identical sequences that have very different structural properties, and these could give rise to false-positives in methods used to identify function based on sequence alignment. A simple validation test demonstrates that structural similarity can differentiate between promoter and non-promoter DNA. Combining structural and sequence similarity improves promoter recall beyond that possible using either similarity measure alone, demonstrating that there is indeed information available in the structure of double-helical DNA that is not readily apparent from the sequence.

DNA↗
PubMed2004

Comparison of topological descriptors for similarity-based virtual screening using multiple bioactive reference structures.

This paper reports a detailed comparison of a range of different types of 2D fingerprints when used for similarity-based virtual screening with multiple reference structures. Experiments with the MDL Drug Data Report database demonstrate the effectiveness of fingerprints that encode circular substructure descriptors generated using the Morgan algorithm. These fingerprints are notably more effective than fingerprints based on a fragment dictionary, on hashing and on topological pharmacophores. The combination of these fingerprints with data fusion based on similarity scores provides both an effective and an efficient approach to virtual screening in lead-discovery programmes.

Algorithms↗
PubMed2004

Alignment of three-dimensional molecules using an image recognition algorithm.

This paper describes a novel approach, based on image recognition in two dimensions, for the atom-based alignment of two rigid molecules in three dimensions. The atoms are characterised by their partial charges and their positions relative to the remaining atoms in the molecule. Based on this information, a cost of matching a pair of atoms, one from each molecule, is assigned to all possible pairs. A preliminary set of intermolecular atom equivalences that minimises the total atom matching cost is then determined using an algorithm for solving the linear assignment problem. Several geometric heuristics are described that aim to reduce the number of atom equivalences that are inconsistent with the 3D structures. Those that remain are used to calculate an alignment transformation that achieves an optimal superposition of atoms that have a similar local geometry and partial charge. This alignment is then refined by calculating a new set of equivalences consisting of atom pairs that are approximately overlaid, irrespective of partial charge. A range of examples is provided to demonstrate the efficiency and effectiveness of the method.

Algorithms↗
PubMed2004

Joint segmentation and classification of time series using class-specific features.

We present an approach for the joint segmentation and classification of a time series. The segmentation is on the basis of a menu of possible statistical models: each of these must be describable in terms of a sufficient statistic, but there is no need for these sufficient statistics to be the same, and these can be as complex (for example, cepstral features or autoregressive coefficients) as fits. All that is needed is the probability density function (PDF) of each sufficient statistic under its own assumed model--presumably this comes from training data, and it is particularly appealing that there is no need at all for a joint statistical characterization of all the statistics. There is similarly no need for an a-priori specification of the number of sections, as the approach uses an appropriate penalization of an over-zealous segmentation. The scheme has two stages. In stage one, rough segmentations are implemented sequentially using a piecewise generalized likelihood ratio (GLR); in the second stage, the results from the first stage (both forward and backward) are refined. The computational burden is remarkably small, approximately linear with the length of the time series, and the method is nicely accurate in terms both of discovered number of segments and of segmentation accuracy. A hybrid of the approach with one based on Gibbs sampling is also presented; this combination is somewhat slower but considerably more accurate.

Journal Article↗
PubMed2004

Evaluation of molecular similarity and molecular diversity methods using biological activity data.

This chapter reviews the techniques available for quantifying the effectiveness of methods for molecular similarity and molecular diversity, focusing in particular on similarity searching and on compound selection procedures. The evaluation criteria considered are based on biological activity data, both qualitative and quantitative, with rather different criteria needing to be used depending on the type of data available.

Molecular Structure↗
PubMed2003

Sequence-dependent DNA structure: a database of octamer structural parameters.

We have constructed the potential energy surfaces for all unique tetramers, hexamers and octamers in double helical DNA, as a function of the two principal degrees of freedom, slide and shift at the central step. From these potential energy maps, we have calculated a database of structural and flexibility properties for each of these sequences. These properties include: the values of each of the six step parameters (twist roll, tilt, rise, slide and shift), for each step of the sequence; flexibility measures for both decrease and increase in each property value from the minimum energy conformation for the central step; and the deviation from the path of a hypothetical straight octamer. In an analysis of structural change as a function of sequence length, we observe that almost all DNA tends to B-DNA and becomes less flexible. A more detailed analysis of octamer properties has allowed us to determine the structural preferences of particular sequence elements. GGC and GCC sequences tend to confer bistability, low stability and a predisposition to A-form DNA, whereas AA steps strongly prefer B-DNA and inhibit A-structures. There is no correlation between flexibility and intrinsic curvature, but bent DNA is less stable than straight. The most difficult deformation is undertwisting. The TA step stands out as the most flexible sequence element with respect to decreasing twist and increasing roll. However, as with the structural properties, this behavior is highly context-dependent and some TA steps are very straight.

DNA↗
PubMed2003

GAPDOCK: a Genetic Algorithm Approach to Protein Docking in CAPRI round 1.

As part of the first Critical Assessment of PRotein Interactions, round 1, we predict the structure of two protein-protein complexes, by using a genetic algorithm, GAPDOCK, in combination with surface complementarity, buried surface area, biochemical information, and human intervention. Among the five models submitted for target 1, HPr phosphocarrier protein (B. subtilis) and the hexameric HPr kinase (L. lactis), the best correctly predicts 17 of 52 interprotein contacts, whereas for target 2, bovine rotavirus VP6 protein-monoclonal antibody, the best model predicts 27 of 52 correct contacts. Given the difficult nature of the targets, these predictions are very encouraging and compare well with those obtained by other methods. Nevertheless, it is clear that there is a need for improved methods for distinguishing between "correct" and "plausible but incorrect" complexes.

Algorithms↗
PubMed2003

Comparison of chemical clustering methods using graph- and fingerprint-based similarity measures.

This paper compares several published methods for clustering chemical structures, using both graph- and fingerprint-based similarity measures. The clusterings from each method were compared to determine the degree of cluster overlap. Each method was also evaluated on how well it grouped structures into clusters possessing a non-trivial substructural commonality. The methods which employ adjustable parameters were tested to determine the stability of each parameter for datasets of varying size and composition. Our experiments suggest that both graph- and fingerprint-based similarity measures can be used effectively for generating chemical clusterings; it is also suggested that the CAST and Yin-Chen methods, suggested recently for the clustering of gene expression patterns, may also prove effective for the clustering of 2D chemical structures.

Algorithms↗
PubMed2003

Representation, searching and discovery of patterns of bases in complex RNA structures.

We describe a graph theoretic method designed to perform efficient searches for substructural patterns in nucleic acid structural coordinate databases using a simplified vectorial representation. Two vectors represent each nucleic acid base and the relative positions of bases with respect to one another are described in terms of distances between the defined start and end points of the vectors on each base. These points comprise the nodes and the distances the edges of a graph, and a pattern search can then be performed using a subgraph isomorphism algorithm. The minimal representation was designed to facilitate searches for complex patterns but was first tested on simple, well-characterised arrangements of bases such as base pairs and GNRA-tetraloop receptor interactions. The method performed very well for these interaction types. A survey of side-by-side base interactions, of which the adenosine platform is the best known example, also locates examples of similar base rearrangements that we consider to be important in structural regulation. A number of examples were found, with GU platforms being particularly prevalent. A GC platform in the RNA of the Thermus thermophilus small ribosomal subunit is in an analogous position to an adenosine platform in other species. An unusual GG platform is also observed close to one of the substrate binding sites in Haloarcula marismortui large ribosomal subunit RNA.

Base Pairing↗
PubMed2002

A sphere-based descriptor for matching protein structures.

This paper describes the use of a descriptor based on the number of alpha-carbon atoms within a sphere centered on the alpha-carbon in each amino acid residue in a protein. The descriptor can be used instead of the residue types in a dynamic programming algorithm, thus providing an efficient way of aligning protein structures. The method is applied to the alignment of protein families and to database searching. The results indicate that the method can quickly align protein sequences considering the 3D structure and can find proteins that are 3D structurally similar and dissimilar to the target protein.

Amino Acid Sequence↗
PubMed2002

Designing focused libraries using MoSELECT.

When designing a combinatorial library it is usually desirable to optimise multiple properties of the library simultaneously and often the properties are in competition with one another. For example, a library that is designed to be focused around a given target molecule should ideally have minimum cost and also contain molecules that are bioavailable. In this paper, we describe the program MoSELECT for multiobjective library design that is based on a multiobjective genetic algorithm (MOGA). MoSELECT searches the product-space of a virtual combinatorial library to generate a family of equivalent solutions where each solution represents a combinatorial subset of the virtual library optimised over multiple objectives. The family of solutions allows the relationships between the objectives to be explored and thus enables the library designer to make an informed choice on an appropriate compromise solution. Experiments are reported where MoSELECT has been applied to the design of various focused libraries.

Algorithms↗