Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space.

Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.

Therapeutic Potential of the Modulation of Sphingosine-1-Phosphate Receptors.

It is accepted that sphingolipids (SL) are not only structural lipids in cellular membranes, but also key regulators of different cell process. Sphingosine-1-phosphate (S1P) is a member of this family involved, inter alia, in cell migration, angiogenesis and cell proliferation processes, being able to play different intracellular and extracellular roles. When S1P is transported out of the cell, it binds S1P specific G protein-coupled receptors, which are mainly involved in the regulation of the immune, vascular and nervous systems. These effects account for the vast diversity of functions that arise from the activation of S1P receptors. Deregulation of S1P levels is correlated with several pathologies, such as autoimmune disorders and cancer. Consequently, the correct modulation of these receptors represents a valuable approach for the development of new therapeutic strategies. Along this line, the non-selective S1P receptor agonist fingolimod (FTY720) has been commercialized recently for the treatment of multiple sclerosis and several related S1P receptor modulators are ongoing clinical trials. However, despite the progress in this field, the biological functions of S1P receptors are not still well elucidated. For this reason, several studies are being developed in order to better understand the functions of these receptors, making use of new selective S1P receptor agonists and antagonists as pharmacological tools.