RATIONAL DESIGN OF ANTISICKLING AGENTS

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DESCRIPTION (Adapted from applicant's abstract) The applicant's career goal is to seek a research position in a reputable Institution. His primary goal would be to establish rigorous research programs involving structure-based drug design to find the origin, causes, treatment and prevention of tropical diseases, such as sickle cell anemia, malaria, and sleeping sickness. Furthermore, it is anticipated that molecular modeling techniques unique to the problems to be encountered will be developed to improve the efficiency of the drug development process. To reach these goals, would require considerable experience and skills in drug designing process. Therefore, under the direction of his mentor, he intends to initiate a career development research program involving rational development of compounds to treat sickle cell anemia. This would help him gain the necessary skills and experience to develop his career as an independent researcher. Below is a brief description of the proposal research. A group of halogenated aromatic compounds are known to bind to hemoglobin and show potential as antisickling agents. These compounds bind to the surface of the protein and may explain the antisickling properties. The long term-goal of this research project is to utilize the above information to design and develop stereospecific agents to bind with high affinity to the surface of the hemoglobin for more potent antisickling agents. In addition, both the T and R-state hemoglobins will be used to study structure-function activities. Therefore, the specific aims are: 1) determine and refine the crystal structures of the deoxygenated hemoglobin co-crystallized with halogenated aromatic acids; 2) determine and refine the crystal structures of carbonmonoxy hemoglobin bound with halogenated aromatic acid; 3) rational design of new stereospecific compounds to bind to known binding sites at the surface of the hemoglobin, and other newly identified binding sites; and 4) biological evaluation of the designed compounds for antisickling, antigelling and allosteric activities.