Invited Speaker

Allosteric Regulation of Hemoglobin – Structure-Based Drug Design Approach to Treat Ischemic Related Cardiovascular Diseases
Martin K. Safo

Certain cardiovascular diseases, such as angina, stroke and trauma occur as a result of decreased blood flow to organs; hence these organs receive less oxygen than they need. Insufficient blood supply is called ischemia. Hemoglobin (Hb) is an allosteric tetrameric protein that exists between the deoxy (T or Tense) and oxy (R or relaxed) states. It is composed of two ?? dimers that are arranged around a 2-fold axis of symmetry. This arrangement yields a large central water cavity in the deoxy state, and a narrower cavity in the oxy state. An indigenous allosteric effector of Hb, 2,3 diphosphoglycerate preferentially stabilizes deoxy Hb by forming intermolecular salt bridges between the two ? subunits. This added stabilization decreases the affinity of Hb for oxygen, and subsequently allows for the release of more oxygen in the cardiovascular periphery. We have designed and synthesized a variety of organic molecules that bind to the central water cavity of deoxy Hb. These molecules lower the oxygen affinity of Hb in a physiologically similar fashion as 2,3 diphosphoglycerate, and thus have potential therapeutic application in treating ischemic-related cardiovascular diseases.