329 results found
Reynolds CR, Muggleton SH, Sternberg MJE, 2015, Incorporating virtual reactions into a logic-based ligand-based virtual screening method to discover new leads, Molecular Informatics, Vol: 34, Pages: 615-625, ISSN: 1868-1751
The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs.
Lewis TE, Sillitoe I, Andreeva A, et al., 2015, Genome3D: exploiting structure to help users understand their sequences, NUCLEIC ACIDS RESEARCH, Vol: 43, Pages: D382-D386, ISSN: 0305-1048
Di Fruscia P, Zacharioudakis E, Liu C, et al., 2015, The Discovery of a Highly Selective 5,6,7,8-Tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidin-4(3H)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson's Disease Model, CHEMMEDCHEM, Vol: 10, Pages: 69-82, ISSN: 1860-7179
Irimia M, Weatheritt RJ, Ellis JD, et al., 2014, A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains, Cell, Vol: 159, Pages: 1511-1523, ISSN: 0092-8674
Alternative splicing (AS) generates vast transcriptomicand proteomic complexity. However, whichof the myriad of detected AS events provide importantbiological functions is not well understood.Here, we define the largest program of functionallycoordinated, neural-regulated AS described to datein mammals. Relative to all other types of AS withinthis program, 3-15 nucleotide ‘‘microexons’’ displaythe most striking evolutionary conservation andswitch-like regulation. These microexons modulatethe function of interaction domains of proteinsinvolved in neurogenesis. Most neural microexonsare regulated by the neuronal-specific splicing factornSR100/SRRM4, through its binding to adjacentintronic enhancer motifs. Neural microexons arefrequently misregulated in the brains of individualswith autism spectrum disorder, and this misregulationis associated with reduced levels of nSR100.The results thus reveal a highly conserved programof dynamic microexon regulation associated withthe remodeling of protein-interaction networks duringneurogenesis, the misregulation of which islinked to autism.
Talman AM, Prieto JH, Marques S, et al., 2014, Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility, MALARIA JOURNAL, Vol: 13, ISSN: 1475-2875
Yates CM, Filippis I, Kelley LA, et al., 2014, SuSPect: Enhanced Prediction of Single Amino Acid Variant (SAV) Phenotype Using Network Features, JOURNAL OF MOLECULAR BIOLOGY, Vol: 426, Pages: 2692-2701, ISSN: 0022-2836
Yates CM, Sternberg MJE, 2013, The Effects of Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) on Protein Protein Interactions, JOURNAL OF MOLECULAR BIOLOGY, Vol: 425, Pages: 3949-3963, ISSN: 0022-2836
Alexov E, Sternberg M, 2013, Understanding molecular effects of naturally occurring genetic differences., J Mol Biol, Vol: 425, Pages: 3911-3913
Adzhubei AA, Sternberg MJE, Makarov AA, 2013, Polyproline-II Helix in Proteins: Structure and Function, JOURNAL OF MOLECULAR BIOLOGY, Vol: 425, Pages: 2100-2132, ISSN: 0022-2836
Yates CM, Sternberg MJE, 2013, Proteins and Domains Vary in Their Tolerance of Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs), JOURNAL OF MOLECULAR BIOLOGY, Vol: 425, Pages: 1274-1286, ISSN: 0022-2836
Bryant WA, Sternberg MJE, Pinney JW, 2013, AMBIENT: Active Modules for Bipartite Networks - using high-throughput transcriptomic data to dissect metabolic response, BMC SYSTEMS BIOLOGY, Vol: 7, ISSN: 1752-0509
Radivojac P, Clark WT, Oron TR, et al., 2013, A large-scale evaluation of computational protein function prediction, NATURE METHODS, Vol: 10, Pages: 221-227, ISSN: 1548-7091
Mao C, Shukla M, Larrouy-Maumus G, et al., 2013, Functional assignment of Mycobacterium tuberculosis proteome revealed by genome-scale fold-recognition, TUBERCULOSIS, Vol: 93, Pages: 40-46, ISSN: 1472-9792
Janin J, Sternberg MJE, 2013, Protein flexibility, not disorder, is intrinsic to molecular recognition., F1000 Biol Rep, Vol: 5, ISSN: 1757-594X
An 'intrinsically disordered protein' (IDP) is assumed to be unfolded in the cell and perform its biological function in that state. We contend that most intrinsically disordered proteins are in fact proteins waiting for a partner (PWPs), parts of a multi-component complex that do not fold correctly in the absence of other components. Flexibility, not disorder, is an intrinsic property of proteins, exemplified by X-ray structures of many enzymes and protein-protein complexes. Disorder is often observed with purified proteins in vitro and sometimes also in crystals, where it is difficult to distinguish from flexibility. In the crowded environment of the cell, disorder is not compatible with the known mechanisms of protein-protein recognition, and, foremost, with its specificity. The self-assembly of multi-component complexes may, nevertheless, involve the specific recognition of nascent polypeptide chains that are incompletely folded, but then disorder is transient, and it must remain under the control of molecular chaperones and of the quality control apparatus that obviates the toxic effects it can have on the cell.
Lewis TE, Sillitoe I, Andreeva A, et al., 2013, Genome3D: a UK collaborative project to annotate genomic sequences with predicted 3D structures based on SCOP and CATH domains, Nucleic Acids Res, Vol: 41, Pages: D499-D507, ISSN: 1362-4962
Genome3D, available at http://www.genome3d.eu, is a new collaborative project that integrates UK-based structural resources to provide a unique perspective on sequence-structure-function relationships. Leading structure prediction resources (DomSerf, FUGUE, Gene3D, pDomTHREADER, Phyre and SUPERFAMILY) provide annotations for UniProt sequences to indicate the locations of structural domains (structural annotations) and their 3D structures (structural models). Structural annotations and 3D model predictions are currently available for three model genomes (Homo sapiens, E. coli and baker's yeast), and the project will extend to other genomes in the near future. As these resources exploit different strategies for predicting structures, the main aim of Genome3D is to enable comparisons between all the resources so that biologists can see where predictions agree and are therefore more trusted. Furthermore, as these methods differ in whether they build their predictions using CATH or SCOP, Genome3D also contains the first official mapping between these two databases. This has identified pairs of similar superfamilies from the two resources at various degrees of consensus (532 bronze pairs, 527 silver pairs and 370 gold pairs).
David A, Kelley LA, Sternberg MJE, 2012, A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 49, Pages: 213-220, ISSN: 0952-5041
Sternberg MJE, Tamaddoni-Nezhad A, Lesk VI, et al., 2012, Gene Function Hypotheses for the Campylobacter jejuni Glycome Generated by a Logic-Based Approach, Journal of Molecular Biology, Vol: 425, Pages: 186-197, ISSN: 1089-8638
Increasingly, experimental data on biological systems are obtained from several sources and computational approaches are required to integrate this information and derive models for the function of the system. Here, we demonstrate the power of a logic-based machine learning approach to propose hypotheses for gene function integrating information from two diverse experimental approaches. Specifically, we use inductive logic programming that automatically proposes hypotheses explaining the empirical data with respect to logically encoded background knowledge. We study the capsular polysaccharide biosynthetic pathway of the major human gastrointestinal pathogen Campylobacter jejuni. We consider several key steps in the formation of capsular polysaccharide consisting of 15 genes of which 8 have assigned function, and we explore the extent to which functions can be hypothesised for the remaining 7. Two sources of experimental data provide the information for learning—the results of knockout experiments on the genes involved in capsule formation and the absence/presence of capsule genes in a multitude of strains of different serotypes. The machine learning uses the pathway structure as background knowledge. We propose assignments of specific genes to five previously unassigned reaction steps. For four of these steps, there was an unambiguous optimal assignment of gene to reaction, and to the fifth, there were three candidate genes. Several of these assignments were consistent with additional experimental results. We therefore show that the logic-based methodology provides a robust strategy to integrate results from different experimental approaches and propose hypotheses for the behaviour of a biological system.
Lin D, Chen J, Watanabe H, et al., 2012, Does multi-clause learning help in real-world applications?, Pages: 221-237, ISSN: 0302-9743
The ILP system Progol is incomplete in not being able to generalise a single example to multiple clauses. This limitation is referred as single-clause learning (SCL) in this paper. However, according to the Blumer bound, incomplete learners such as Progol can have higher predictive accuracy while use less search than more complete learners. This issue is particularly relevant in real-world problems, in which it is unclear whether the unknown target theory or its approximation is within the hypothesis space of the incomplete learner. This paper uses two real-world applications in systems biology to study whether it is necessary to have complete multi-clause learning (MCL) methods, which is computationally expensive but capable of deriving multi-clause hypotheses that is in the systems level. The experimental results show that in both applications there do exist datasets, in which MCL has significantly higher predictive accuracies than SCL. On the other hand, MCL does not outperform SCL all the time due to the existence of the target hypothesis or its approximations within the hypothesis space of SCL. © 2012 Springer-Verlag Berlin Heidelberg.
Wass MN, Stanway R, Blagborough AM, et al., 2012, Proteomic analysis of Plasmodium in the mosquito: progress and pitfalls, Parasitology, Vol: 139, Pages: 1131-1145, ISSN: 1469-8161
Here we discuss proteomic analyses of whole cell preparations of the mosquito stages of malaria parasite development (i.e.gametocytes, microgamete, ookinete, oocyst and sporozoite) of Plasmodium berghei. We also include critiques of theproteomes of two cell fractions from the purified ookinete, namely the micronemes and cell surface. Whereas we summarisekey biological interpretations of the data, we also try to identify key methodological constraints we have met, only some ofwhich we were able to resolve. Recognising the need to translate the potential of current genome sequencing into functionalunderstanding, we report our efforts to develop more powerful combinations of methods for the in silico prediction ofprotein function and location. We have applied this analysis to the proteome of the male gamete, a cell whose very simplestructural organisation facilitated interpretation of data. Some of the in silico predictions made have now been supported byongoing protein tagging and genetic knockout studies. We hope this discussion may assist future studies.
Santos JCA, Nassif H, Page D, et al., 2012, Automated identification of protein-ligand interaction features using Inductive Logic Programming: a hexose binding case study, BMC BIOINFORMATICS, Vol: 13, ISSN: 1471-2105
Wass MN, Barton G, Sternberg MJE, 2012, CombFunc: predicting protein function using heterogeneous data sources, NUCLEIC ACIDS RESEARCH, Vol: 40, Pages: W466-W470, ISSN: 0305-1048
Reynolds CR, Amini AC, Muggleton SH, et al., 2012, Assessment of a Rule-Based Virtual Screening Technology (INDDEx) on a Benchmark Data Set, JOURNAL OF PHYSICAL CHEMISTRY B, Vol: 116, Pages: 6732-6739, ISSN: 1520-6106
Phan HTT, Sternberg MJE, 2012, PINALOG: a novel approach to align protein interaction networks-implications for complex detection and function prediction, BIOINFORMATICS, Vol: 28, Pages: 1239-1245, ISSN: 1367-4803
David A, Razali R, Wass MN, et al., 2012, Protein-Protein Interaction Sites are Hot Spots for Disease-Associated Nonsynonymous SNPs, HUMAN MUTATION, Vol: 33, Pages: 359-363, ISSN: 1059-7794
Di Fruscia P, Ho K-K, Laohasinnarong S, et al., 2012, The discovery of novel 10,11-dihydro-5H-dibenz[b,f]azepine SIRT2 inhibitors, MedChemComm
Chambers JC, Zhang W, Sehmi J, et al., 2011, Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma, NATURE GENETICS, Vol: 43, Pages: 1131-1138, ISSN: 1061-4036
Ehret GB, Munroe PB, Rice KM, et al., 2011, Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk, NATURE, Vol: 478, Pages: 103-109, ISSN: 0028-0836
Mitson M, Kelley LA, Sternberg MJE, et al., 2011, Functional significance of mutations in the Snf2 domain of ATRX, HUMAN MOLECULAR GENETICS, Vol: 20, Pages: 2603-2610, ISSN: 0964-6906
Wass MN, David A, Sternberg MJE, 2011, Challenges for the prediction of macromolecular interactions, CURRENT OPINION IN STRUCTURAL BIOLOGY, Vol: 21, Pages: 382-390, ISSN: 0959-440X
Muggleton SH, Chen J, Watanabe H, et al., 2011, Variation of Background Knowledge in an Industrial Application of ILP, 20th International Conference on Inductive Logic Programming (ILP), Publisher: SPRINGER-VERLAG BERLIN, Pages: 158-170, ISSN: 0302-9743
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