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

J Comput Aided Mol Des. 2006 Sep;20(9):567-87. doi: 10.1007/s10822-006-9082-y. Epub 2006 Oct 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Binding Sites
  • Computational Biology / methods*
  • Cyclin-Dependent Kinase 2 / chemistry
  • Cyclin-Dependent Kinase 2 / metabolism
  • Databases, Protein
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • Ligands*
  • Models, Molecular*
  • Molecular Structure
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Software*
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Thermolysin / chemistry
  • Thermolysin / metabolism
  • Thrombin / chemistry
  • Thrombin / metabolism

Substances

  • Ligands
  • Pharmaceutical Preparations
  • Tetrahydrofolate Dehydrogenase
  • Cyclin-Dependent Kinase 2
  • HIV Reverse Transcriptase
  • Thrombin
  • Thermolysin