Lead identification
It was shown that homology models are valuable tools for small molecule design in the lead identification phase of drug discovery.

Design of tool compounds

The number of studies was published, showing the possibility of designing highly selective small molecules, provided, that the structural information is available on all of the relevant homologues of the target. This is one of the cases where the protein structure prediction methods are of great help. Tool compounds designed this way contribute to the elucidation of the physiological roles of the target protein1.

Homology models as tools in ligand design

Protein models obtained using structure prediction methods are often used as molecular design tools allowing the increase of both the affinity and selectivity of small molecular drugs2,3,4. This is visible especially in the field of GPCR research (GPCR ligands constitute ~40% of marketed drugs. Currently experimental structures of only two GPCRs are known, therefore homology modeling becomes the method of choice to obtain the structural information on ligand binding site. Template based modeling can be combined with de novo approaches, allowing the prediction of extracellular loops, that were shown to participate in ligand binding5,6.
  1. Hillisch, A. et al. (2004) Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structurebased design. Mol. Endocrinol. 18, 1599-1609
  2. Traxler, P. et al. (1997) Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R. J. Pharm. Belg. 52, 88-96
  3. Ghosh, S. et al. (2001) Rational design of potent and selective EGFR tyrosine kinase inhibitors as anticancer agents. Curr. Cancer Drug Targets 1, 129-140
  4. Vankayalapati, H. et al. (2003) Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design. Mol. Cancer Ther. 2, 283-294
  5. Shi L, Javitch JA., (2004) The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. Proc Natl Acad Sci U S A. 101(2):440-5
  6. Shi L, Javitch JA., (2002) The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop. Annu Rev Pharmacol Toxicol. 42:437-67