On the integration of in silico drug design methods for drug repurposing

Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease associations

Synthesis and Evaluation of Dual-Acting Ligands for Mu Opioid And Neuropeptide FF Receptors

Pain, although subjective, is an unpleasant sensation caused by a noxious stimulus, that effects millions of people every year. Currently, the most frequently prescribed class of analgesics for moderate to severe acute and sometime chronic pain are opioid analgesics, most commonly ?-opioid receptor (MOP) agonists, such as oxycodone, morphine, and fentanyl. Although these drugs provide significant pain relief, they are also associated with unwelcome side effects such as constipation, addiction, physical dependence, respiratory depression, and physiological tolerance that leads to hyperalgesia. Receptor desensitization due to excessive receptor activation by an agonist is but one source of physiological tolerance; it can also develop through the activation of homeostasis-regulating endogenous anti-opioid systems. One of these anti-opioid systems, the neuropeptide FF (NPFF) system, which is comprised of two receptor subtypes NPFF1 and NPFF2, is a member of the RFamide family and has been shown to modulate opioid activity. Although, currently, there are limited numbers of reported NPFFR ligands, it has been indicated that antagonism of NPFFR leads to the attenuation of physiological tolerance. Currently, many of these ligands are peptidic in structure and are not considered ideal candidates for drug development. However, the design and synthesis of small molecule, dual-acting ligands that act as MOP agonists and NPFF antagonists are a viable approach to opioid analgesics. These ligands would provide the necessary opportunity to provide analgesia, while also blocking a physiological tolerance development center, thus preventing the development of hyperalgesia as well as provide an opioid drug class with reduced side effect liabilities

Chemoisosterism in the Proteome

The concept of chemoisosterism of protein environments is introduced as the complementary property to bioisosterism of chemical fragments. In the same way that two chemical fragments are considered bioisosteric if they can bind to the same protein environment, two protein environments will be considered chemoisosteric if they can interact with the same chemical fragment. The basis for the identification of chemoisosteric relationships among protein environments was the increasing amount of crystal structures available currently for protein–ligand complexes. It is shown that one can recover the right location and orientation of chemical fragments constituting the native ligand in a nuclear receptor structure by using only chemoisosteric environments present in enzyme structures. Examples of the potential applicability of chemoisosterism in fragment-based drug discovery are provided