caa a22 4500 467938733 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060901xx s 000 0 eng 10.1007/s10822-006-9082-y doi (NATIONALLICENCE)springer-10.1007/s10822-006-9082-y GALAHAD: 1. Pharmacophore identification by hypermolecular alignment of ligands in 3D [Elektronische Daten] [Nicola Richmond, Charlene Abrams, Philippa Wolohan, Edmond Abrahamian, Peter Willett, Robert Clark] Summary: 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. Springer Science+Business Media, LLC, 2006 GALAHAD nationallicence Hypermolecule nationallicence Hyperstructure nationallicence Molecular alignment nationallicence Pharmacophore nationallicence Pharmacostere nationallicence Shape similarity nationallicence ATP : Adenosine triphosphate nationallicence CDK-2 : Cyclin dependent kinase 2 nationallicence DHFR : Dihydrofolate reductase nationallicence GALAHAD : A Genetic Algorithm with Linear Assignment for the Hypermolecular Alignment of Datasets nationallicence GASP : Genetic Algorithm Superposition Program nationallicence GPCR : G-Protein coupled receptor nationallicence HIV-1 : Human immunodeficiency virus 1 nationallicence LAMDA : Linear Assignment for Molecular 50 Dataset Alignment nationallicence LAP : Linear assignment problem nationallicence MCS : Maximum common subgraph nationallicence RMSD : Root mean square deviation nationallicence RT : Reverse transcriptase nationallicence Richmond Nicola Krebs Institute for Biomolecular Research, Department of Information Studies, University of Sheffield, 211 Portobello St., S7 4DP, Sheffield, UK aut Abrams Charlene Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut Wolohan Philippa Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut Abrahamian Edmond Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut Willett Peter Krebs Institute for Biomolecular Research, Department of Information Studies, University of Sheffield, 211 Portobello St., S7 4DP, Sheffield, UK aut Clark Robert Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/9(2006-09-01), 567-587 0920-654X 20:9<567 2006 20 10822 https://doi.org/10.1007/s10822-006-9082-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9082-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Richmond Nicola Krebs Institute for Biomolecular Research, Department of Information Studies, University of Sheffield, 211 Portobello St., S7 4DP, Sheffield, UK aut NATIONALLICENCE 700 1- Abrams Charlene Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Wolohan Philippa Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Abrahamian Edmond Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Willett Peter Krebs Institute for Biomolecular Research, Department of Information Studies, University of Sheffield, 211 Portobello St., S7 4DP, Sheffield, UK aut NATIONALLICENCE 700 1- Clark Robert Informatics Research Center, Tripos Inc., 1699 South Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/9(2006-09-01), 567-587 0920-654X 20:9<567 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer