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Sickle cell disease (SCD) is a chronic hemolytic disease caused by an altered hemoglobin molecule (HbS) and was first termed as a molecular disease. Glutamic acid in the normal hemoglobin molecule (HbA), was replaced by valine in HbS at the sixth position of both β-chains. This alteration was proved to be due to a single point mutation GTG instead of GAG in the genetic code. Since the discovery of sickle cell disease in 1910, great efforts have been done to study this disease on a molecular level. These efforts aimed to identify the disease etiology, pathophysiology, and finally to discover efficient treatment. Despite the tremendous work of many research groups all over the world, the only approved drug up to this moment, for the treatment of SCD is the hydroxyurea. In this review, the antisickling pharmaco-therapeutics will be classified into two major groups: hemoglobin site directed modifiers and ex-hemoglobin effectors. The first class will be discussed in details, here in, focusing on the most important figures in the way of the rational drug design for SCD treatment aiming to help scientists solve the mystery of this problem and to get clear vision toward possible required therapy for SCD. Despite the large number of the antisickling candidates that have been reached clinical studies yet, none of them has been introduced to the market. This may be due to the fact that hemoglobin is a large molecule with different target sites, which requires highly potent therapeutic agent. With this potency, these drugs should be safe, with acceptable oral pharmacokinetic and pharmacodynamic properties. Such ideal drug candidate needs more efforts to be developed.

100 years of sickle cell disease research: etiology, pathophysiology and rational drug design (part 1)