Pharmaceutical Targets
E&A scientists, with specialized experience and knowledge in biomolecular recognition and cellular signal transduction, can detect new specific targets for drug design and discovery. They can add the missing links, as shown in the figure below, by scrutinizing and complementing knowledge about a specific signal transduction pathway. The E&A team then designs lead compounds capable of interacting with the targets in the pathway.
The figure details the Type I Interferon/ds-RNA-dependent protein kinase (PKR) pathway and identifies various targets in the pathway such as PKR itself, but also the p38 MAP kinase, cyclooxygenase-2 (COX-2), and the inducible nitric oxide synthetase (iNOS). The arrows from each target link to families of lead compounds interacting with the target in order to modulate its activity. For more details about identifying targets for drug design, see the following two Acrobat files:
At E&A, we further examine the lead compounds indentified as interacting with their targets by conformational docking. This is how we quantify the interaction of the potential drug with selected residues within the binding site of the target and to design other drug derivatives with improved activity. The process also allows us to create new intellectual property by assessing orginal isosteres. This is illustrated with the next figure.
The figure shows the docking after energy minimization of 5,5-diaryldiazasilole derivatives of Sc-558 and Celecoxib (examples 1 and 2, respectively) within the binding site of COX-2. Examples 3 and 4 show the docking of 3,3-diaryloxazasilole and 2,2-diarylazisiline derivatives of Valdecoxib and Etoricoxib, respectively. Because of an improved H-bonding interaction with key residues in the second binding pocket (R513 and H90), while maintaining good hydrophobic contacts with key residues within the first binding pocket (Y385, W387, S530, L531), these compounds have activities increased at least 10 fold when compared to their parent compounds.
When an experimental crystallographic model of the protein is available from the protein data bank, we use this model as the template for the docking procedure, such as in the above example. In many cases, however, experimental models are not available. In such a case, we are able to design a theoretical model of the protein by homology. Protein Modeling is exemplified in the next figure.
The figure shows a theoretical model obtained by homology, of 2',5'-oligoadenylate synthetase (p49 subunit), an enzyme that polymerizes ATP into 2',5'-oligoadenylates of various sizes. The model is represented in ribbons (left-hand side) and surfaces (right-hand side) colored according to the secondary structure.
Our understanding of various cellular signalling pathways and our familiarity with their possible deregulations in immune and chronic diseases allow us to identify new diagnostic markers for the detection and quantitation of which we are keen to develop specific immunoassays. These analytical techniques further allow us to evaluate these markers in terms of clinical sensitivity and specificity for a given disorder.