The long-term goals of this program (GM-41821) are to explore and develop new concepts in bioorganic/medicinal chemistry, which will be used by colleagues in academia and industry. The principal aim for the next four-year period are to exploit the implications of the pseudosymmetric nature of our beta-D-glucose scaffold. Using the molecular modeling results obtained during the 08-11 years, we will (A) vary the position of the Trp and Lys sidechain mimics on the scaffold seeking improved affinity by providing a better orientation. In the NK receptor ligand project, we will use the molecular modeling results (B) to reduce the number of sidechains and optimize their position to improve binding affinity. We will also seek to (C) modulate receptor subtype selectivity by generating novel interactions with the loop region of the receptor. The ability of our sugars to mimic peptide beta-turns will be used to (D) identify the residues of a cyclic hexapeptide which are critical for binding the GnRH receptor. After obtaining this critical information we will (E) study the solution conformation of the peptide, which will allow us to optimize out ligand design (F) to synthesize a potent GnRH receptor agonist or antagonist based on our sugar scaffold. Since the role that the pyranose oxygen plays in binding the receptor is unclear, we will (G) synthesize a cyclohexane analog of our SRIF ligands to explore this aspect further. Having generated several promiscuous ligands and demonstrated their capacity to bind various biological targets, we will synthesize a small targeted library in order to realize the full potential of the specific scaffold. To achieve this goal, we will (H) devise new synthetic methodology to introduce sidechains containing heterocyclic moieties at either C(4) or C(6). This will allow us to (I) elaborate a targeted library incorporating a C(1) indole aimed at exploring our lead inhibitors in broad screening assays. In this area, we will also (J) seek to exploit our benzodiazepine scaffold to generate a library of tricyclic compounds aimed at broad screening. Finally, we will explore (K) the pharmacokinetic profiles of our lead mimics through our collaborations with expert biologists.
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