RATIONAL DESIGN OF ANTISICKLING AGENTS
Principal Investigator: Martin K Safo
Abstract: 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.
Funding Period: 2000-09-01 - 2005-08-31
more information: NIH RePORT
- The enigma of the liganded hemoglobin end state: a novel quaternary structure of human carbonmonoxy hemoglobinM K Safo
School of Pharmacy, Department of Medicinal Chemistry, and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, USA
Biochemistry 44:8347-59. 2005..The current Hb structure-function relationships that are now based on T --> R, T -->R --> R2, or T --> R2 --> R transitions may have to be reexamined to take into account the RR2 and R3 liganded structures...
- Structures of R- and T-state hemoglobin Bassett: elucidating the structural basis for the low oxygen affinity of a mutant hemoglobinMartin K Safo
Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298, USA
Acta Crystallogr D Biol Crystallogr 61:156-62. 2005..The R- and T-state structures of Hb Bassett suggest a stereochemical basis for the observed functional properties of this mutant...
- 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cellsOsheiza Abdulmalik
Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Br J Haematol 128:552-61. 2005..These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease...