Site Directed Drug Discovery®

7TM receptors (GPCRs) contain a generic protein structure of 7 bundled transmembrane (7TM) helices that is extensively used for a variety of stimuli e.g. photons, monoamines, fatty acids, peptide hormones, and glycoproteins. Despite successful development of drugs for 7TM receptors, efficient structure-based drug discovery is hampered by lack of detailed structural information, since transmembrane receptors are not amenable to X-ray crystallography or NMR; today only one crystal structure (rhodopsin receptor) is available as basis for modeling of receptors.(1)

Traditional drug discovery on 7TM receptors is mostly based on high throughput screening (HTS), which requires substantial investment in chemical libraries, equipment and development of robust assays – an effort that often takes 6-9 months prior to screening, even if progress is being made in miniaturizing and robotizing these processes.(2) After the HTS campaign, substantial post-processing work is required to verify and “deconvolute” the primary screening data to identify and validate true hits.

It is apparent today that the success of HTS is insufficient and the post-processing efforts to arrive at a reduced number of validated hits are substantial. Thus, a tailored approach in the form of smaller targeted libraries, allowing more information-rich assays to be used, has been developed by 7TM Pharma - Site Directed Drug Discovery®. The basis to improve the drug design process is the identification of receptors already associated with ligand information (e.g. ligands with mutagenesis or SAR data) and closely related to the target receptor. A protocol has been developed to relate 7TM receptor proteins with respect to the physicochemical nature in the binding site for their ligands.(4) Proprietary software tools are utilized for assignment and comparison of physicochemical descriptors to binding site residues. Focus is then directed towards receptors with known ligands and similar binding pockets to support construction of receptor models which are converted into pharmacophore models for in silico screening. Pharmacophore models can also be obtained from sets of known ligands to facilitate lead hopping into other types of chemistries.(3)

A core component of the technology is the design of new ligands and generation of tailor-made chemical libraries based on pharmacophore analysis of the receptor. These target-focused libraries contain generally less than 1,000 compounds, allowing for rapid screening with little downstream processing work that generates high content information for each compound. 7TM Pharma has demonstrated this approach on a number of different receptors with completion of the entire cycle within 3-4 months until identification of first hit sets. This rapid process allows prioritization of potential drug targets based on biological validation and on chemical tractability.

(1) Lundstrom K (2005). Bioorg. Med. Chem. Lett. 15: 3654-3657
(2) Högberg T (2005). Drug Discov. Today 12: 820-822
(3) Ulven T et al. (2005). J. Med. Chem. 48: 5684-5697
(4) Frimurer TM et al (2005). Bioorg. Med. Chem. Lett. 15: 3707-3712