X-ray crystallography and sickle cell disease drug discovery—a tribute to Donald Abraham

Frontiers in Molecular Biosciences

Molecular Biosciences

Akua K. Donkor¹  Piyusha P. Pagare¹  Mohammed H. AL Mughram¹  Martin K. Safo² 

[1] Department of Medicinal Chemistry and the Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States;null;

关键词: X-ray crystallography;    structure-based drug discovery;    aromatic aldehydes;    sickle cell disease;    hemoglobin;    oxygen affinity;    antisickling;    allosteric effectors;   

DOI  :  10.3389/fmolb.2023.1136970

 received in 2023-01-03, accepted in 2023-05-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

X-ray crystallography and structure-based drug discovery have played a major role in the discovery of antisickling agents that target hemoglobin (Hb) for the treatment of sickle cell disease (SCD). Sickle cell disease, the most common inherited hematologic disorder, occurs as a result of a single point mutation of βGlu6 in normal human adult hemoglobin (HbA) to βVal6 in sickle hemoglobin (HbS). The disease is characterized by polymerization of HbS and sickling of red blood cells (RBCs), leading to several secondary pathophysiologies, including but not limited to vaso-occlusion, hemolytic anemia, oxidative stress, inflammation, stroke, pain crisis, and organ damage. Despite the fact that SCD was the first disease to have its molecular basis established, the development of therapies was for a very long time a challenge and took several decades to find therapeutic agents. The determination of the crystal structure of Hb by Max Perutz in the early 60s, and the pioneering X-ray crystallography research by Donald J. Abraham in the early 80s, which resulted in the first structures of Hb in complex with small molecule allosteric effectors of Hb, gave much hope that structure-based drug discovery (SBDD) could be used to accelerate development of antisickling drugs that target the primary pathophysiology of hypoxia-induced HbS polymerization to treat SCD. This article, which is dedicated to Donald J. Abraham, briefly reviews structural biology, X-ray crystallography and structure-based drug discovery from the perspective of Hb. The review also presents the impact of X-ray crystallography in SCD drug development using Hb as a target, emphasizing the major and important contributions by Don Abraham in this field.

【 授权许可】

Unknown   
Copyright © 2023 Donkor, Pagare, Mughram and Safo.