The challenging questionof the modern pharmaceutical industryis why do fragments hits provide a new paradigm for drug discovery of some targets? In this white paper 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 complementarities 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 speciallydesigned Fragment Library to providechemicalfragmentsthat can be starting points for drug discovery.This library construction was performed using strict structural, substructural and special medicinal chemistry filters.This OTAVA’s Fragment Library, comprising approximately 3,800 compounds, has been designed using the commonly accepted Rule-of-Three(MW ≤ 300, H-bond donors ≤ 3, H-bond acceptors ≤ 3, cLogP ≤ 3).Selected compounds possess good aqueous solubility what is essential for practical reasons during screenings (particularly in High Concentration Screening (HCS)).Compounds containing functionalities that can cause undesirable effects such as cancerogenic, toxicity, ADME problems and 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 in drug discovery.