Bioactivity protein interactions

An application of the ROCS program has been reported recently (82). New scaffolds for small molecule inhibitors of the ZipA-FtsZ protein-protein interaction have been found. The shape comparisons are made relative to the bioactive conformation of a HTS hit, determined by X-ray crystallography. A followup X-ray crystallographic analysis also showed that ROCS accurately predicted the binding mode of the inhibitor. This result offers the first experimental evidence that validates the use of ROCS for scaffold hopping purposes. 

For this discussion, bioactive peptides will be defined as peptides which interact specifically with a target macromolecular acceptor or are derived from domains involved in a critical protein-protein interaction and, therefore, can compete effectively to mimic or disrupt this bimolecular interaction. Once the structure-activity relationship of a bioactive peptide is revealed, one can identify the termini and/or positions in which introduction of a caging group will be disruptive for target recognition. Alternatively, caging the peptide in an inactive conformation can be accomplished by end-to-end or end-to-side-chain cyclization. 

As of 2008, 25 therapeutic monoclonal antibodies (mAbs) mAbs had been approved for clinical use in the United States, and with over 400 antibodies being in preclinical and clinical development further increase of antibody therapies is assured (10, 11). As a general rule, the Fc fragment is a key component of therapeutic mAb design because it extends their pharmacokinetics. Inclusion of the Fc from IgG is also a key component of other bioactive proteins where prolongation of pharmacokinetics is desired, e.g., the tumor necrosis factor receptor (TNFR) fusion protein etan-ercept (Enbrel ) (12). Thus for both therapeutic antibodies and Fc-fusion proteins, the FcRn interaction is a generalized way to exploit FcRn protection to achieve the benefits of extended persistence in vivo. 

Study of interactions of bioactive proteins/peptides/amino acids with other food components during processing and effects of these interactions on bioactivity. 

Antidiuretic hormone is a posterior pituitary peptide hormone that binds to vasoconstrictive Via receptors (via Gaq to activate PLC and thence increase cytsosolic Ca2+), to V2 receptors (causing kidney water reabsorption via Gas and increased cAMP) and to corticotropin secretion-regulating Vlb (V3) receptors (mediated by Gaq to activate PLC and thence increase cytosolic Ca2+). For bioactive-G protein interactions see Table 5.9. 

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

The purpose of this chapter is to provide an overview of the application of monosaccharides for the synthesis of novel compounds, and in particular we have focused on bioactive compounds that target protein-protein or peptide-protein interactions. We have not reviewed extensively the application of monosaccharides as scaffolds that modulate carbohydrate-protein interactions (glycomimetics or inhibitors of glycoprocessing enzymes) as these are considered elsewhere. Also it has not been possible to detail all of the work of those groups who have contributed to this area. The review is divided into two main sections synthesis and application of monosaccharides that are SAAs and synthesis and application of monosaccharides that are not SAAs. The structures and applications of the monosaccharide building blocks are considered as are the synthesis and properties of target compounds. 

R245 R. C. Baxter, Insulin-Like Growth Factor (IGF) - Binding Proteins Interactions with IGFs and Intrinsic Bioactivities , Am. J. Physiol., 2000, 278, E967... 

Figure 15.2 illustrates some of the discovery bioactivity experiments in which a test compound must be successful to advance. If erroneous activity or selectivity data are generated or misinterpreted, the SAR will mislead the project team. SAR is a central strategy of drug-discovery research. If the activity assays are affected by properties in addition to target protein interaction, then the SAR will be a composite of multiple variables. Table 15.1 lists some of the potential effects on SAR from lack of property data application in planning and interpretation of drug-discovery bioassays. 

Complexes that feature a-helices at interfaces were studied because a-helices constitute the largest class of protein secondary structure and mediate many protein interactions [30, 51]. Helices located within the protein core are vital for the overall stability of protein tertiary structure, whereas exposed a-helices on protein surfaces constitute central bioactive regions for the recognition of numerous proteins, DNAs, and RNAs. Importantly, helix mimetics have emerged as a highly effective class of PPI inhibitors [32, 36, 44, 52-55]. 

Homans, S.W. (2007) Dynamics and thermodynamics of ligand—protein interactions, in Bioactive Corformation I, vol. 272, Topics in Current Chemistry (ed. T. Peters), Springer, Berlin, pp. 51-82. 

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