Abstract:
:Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly true for G protein-coupled receptors (GPCRs), one of the most important targets for approved medicines and current drug discovery projects. However, very few studies have tested their validity in comparison with corresponding crystal structures, especially in a lead optimization perspective. The recent solving of dopamine D3 receptor crystal structure allowed us to assess our historical homology model. We performed a statistical analysis, by docking our in-house lead optimization library of 1500 molecules. We demonstrate here that the refined homology model suits at least as well as the X-ray structure. It is concluded that when the crystal structure of a given GPCR is not available, homology modeling can be an excellent surrogate to support drug discovery efforts.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Levoin N,Calmels T,Krief S,Danvy D,Berrebi-Bertrand I,Lecomte JM,Schwartz JC,Capet Mdoi
10.1021/ml100288qsubject
Has Abstractpub_date
2011-02-11 00:00:00pages
293-7issue
4issn
1948-5875journal_volume
2pub_type
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