The OTAVA Fragment-Based Library
Résumé
The challenging question of the modern pharmaceutical industry is why do fragment hits provide a new paradigm for drug discovery of some targets? In this press release we describe the advantages of the fragment-based approach in the search for new drugs. Typical drug molecules contain high-molecular weight compounds. Given their large size, these molecules bind to their target receptor inefficiently due to poorly optimized interactions. To achieve a specific and tight fit to the receptor binding site, exact matching of three-dimensional shapes and chemical features are essential. This problem can be solved using target-based screening with smaller molecular units - fragments. Fragments are common scaffolds and ring systems which are frequently observed in drug molecules. Fragments exhibit higher probability of making efficient interactions with different proteins through better complementarity of shapes and electrostatic properties. Fragment hits typically possess high ligand efficiency (binding affinity per heavy atom) thus they are highly suitable for optimization to get clinical candidates with good drug-like properties. Fragments are typically constructed by substituting one or two side-chains on a fragment ring system. Multiple fragments can also be linked to each other to form a single more potent ligand. Understanding the increasing importance of the fragment-based approach for modern pharmaceutical industry, we have designed a library of quality fragments which would provide a useful probing tool to identify bindings to any biological target. OTAVA offers its own specially designed Fragment Library to provide chemical fragments that can be starting points for drug discovery. This library construction was performed using strict structural, substructural and special medicinal chemistry filters. The OTAVA's Fragment Library, comprising about 8000 compounds, has been designed using the commonly accepted Rule-of-Three (MW ≤ 300, H-bond donors ≤ 3, H-bond acceptors ≤ 3, cLogP ≤ 3). Compounds should possess high aqueous solubility that is essential for practical reasons during screenings (particularly in high-content screening (HCS)). Compounds containing functionalities that can cause undesirable effects such as: Cancerogenic, Toxicity, ADME problems, False positives were removed from the library. The OTAVA Fragment Library has been developed to meet the needs of our customers who are looking for pre-selected fragment products for drug discovery.