GALAHAD: 1. Pharmacophore Identification by Hypermolecular Alignment of Ligands in 3d. Richmond, N. J.; Abrams, C. A.; Wolohan, P. R. N.; Abrahamian, E.; Willett, P.; and Clark, R. D. J.~Comp.~Aided Mol.~Des., 20(9):567--587, SPRINGER, VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS, 2006.
doi  abstract   bibtex   
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.
@article{Richmond:2006aa,
	Abstract = {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.},
	Address = {VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS},
	Author = {Richmond, Nicola J. and Abrams, Charlene A. and Wolohan, Philippa R. N. and Abrahamian, Edmond and Willett, Peter and Clark, Robert D.},
	Date = {SEP 2006},
	Date-Added = {2008-09-14 17:39:01 -0400},
	Date-Modified = {2008-09-14 17:39:43 -0400},
	Doi = {10.1007/s10822-006-9082-y},
	Isi = {000242326300003},
	Isi-Recid = {153391122},
	Isi-Ref-Recids = {128945503 81645100 124024987 86265538 128272864 51415181 153391123 145521462 143280424 66809051 99895854 46505097 94594920 89466874 109015564 153391124 113889762 119785225 50732845 115108975 116456132 127988604 127373996 136585829 153391125 72294263},
	Journal = {J.~Comp.~Aided Mol.~Des.},
	Keywords = {GALAHAD; hypermolecule; hyperstructure; molecular alignment; pharmacophore; pharmacostere; shape similarity; pharmacophore},
	Number = {9},
	Pages = {567--587},
	Publisher = {SPRINGER},
	Timescited = {11},
	Title = {{GALAHAD}: 1. Pharmacophore Identification by Hypermolecular Alignment of Ligands in 3d},
	Volume = {20},
	Year = {2006},
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