DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKLING AGENTS

Virginia Commonwealth University, Richmond VA

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Abstract

The overall goal of this research program is to extend our hemoglobin studies and focus on structure based drug discovery in: a) Structure- Function studies and allosteric effectors as Anti-ischemic Agents and b) Design and Development of Antisickling/Antigelling Agents. Therefore our specific aims include: (1) Design and synthesis of hemoglobin allosteric effectors to further establish structural features within the protein that regulate allostery and can be developed as potential anti-ischemic agents; (2) Oxygen equilibrium and kinetic analyses of the reacted allosteric effectors; (3) X-ray crystallographic structure determination and refinement of HbA-allosteric effector complexes to provide information pertaining to a) the movements of amino acids during the allosteric transition; b) the role of water in the binding of the allosteric probes; and c) the identification of amino acid residues that are key to the regulation of the allosteric equilibrium; (4) rational design and synthesis of new stereospecific transient covalent antisickling agents that will specifically bind to target residues involved in the polymerization of HbS; (5) X-ray crystallographical studies to determine the binding sites of HbA- effector complexes. These will provide the atomic details necessary for rational re-design of molecules to increase their efficacy; (6) Evaluation of the synthesized molecules for antisickling, antigelling and allosteric effector activity by various methods.