Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

Manipulating tissue metabolism by amino acids

Protein metabolism is considered to be regulated by amino acids, with major consequences on tissue development. There is evidence that lysine greatly affects carcass composition and muscle growth. In particular, a drastic effect of dietary provision of lysine has been observed on breast muscle development in chickens. Other essential amino acids, such as threonine and valine, do not have as pronounced an effect as lysine on body composition. Increasing lysine can also improve chicken breast muscle quality by increasing its ultimate pH and water holding capacity, but the underlying mechanisms are still unknown. Studies conducted over the last ten years indicate that, in addition to being substrates for protein synthesis, amino acids act as modulators of signal transduction pathways that control metabolism and cell functions. For instance, certain amino acids can modulate the activity of the intracellular protein kinases involved in the control of mRNA translation. Interestingly, enhanced responses to amino acids have been reported during the neonatal period, suggesting that early protein nutrition impacts on the development of broiler chicks. Methionine and cysteine have a very significant place among amino acids because they have several additional roles: they are precursors of essential molecules, for example cysteine is used for the synthesis of the antioxidant glutathione, and thus participates in the control of oxidative status, methionine is a source of the methyl groups needed for all biological methylation reactions, including methylation of DNA and histones, etc. These findings together indicate the importance of optimizing amino acid nutrition and providing a rationale for nutritional advice. © Copyright World's Poultry Science Association 2011