Mehlin Christopher
University of Washington, Structural Genomics of Pathogenic Protozoa, Box 357350 Department of Biochemistry, Seattle, WA 98195, USA.
Comb Chem High Throughput Screen. 2005 Feb;8(1):5-14. doi: 10.2174/1386207053328093.
X-ray crystallography is a technique which is finding increasing utility in the effort to find new antimalarial drugs. This is in spite of the serious difficulties often encountered in obtaining sufficient quantities of protein to crystallize. This review provides an overview of the Plasmodium falciparum proteins which have been crystallized with bound inhibitors and the methodology employed in the heterologous expression of these proteins. Lactate dehydrogenase, plasmepsin II, and triosphosphate isomerase are the most advanced targets of structure-based drug design, but nine other P. falciparum proteins have been crystallized with inhibitors as well, and this is clearly an area which is moving very quickly. Some consideration will also be given to the limitations of structure-based drug discovery with respect to known antimalarial drugs.
X射线晶体学是一种在寻找新型抗疟药物的过程中越来越有用的技术。尽管在获得足够量的蛋白质以进行结晶时经常遇到严重困难，但情况依然如此。本综述概述了已与结合抑制剂一起结晶的恶性疟原虫蛋白质，以及这些蛋白质异源表达中所采用的方法。乳酸脱氢酶、组织蛋白酶II和磷酸丙糖异构酶是基于结构的药物设计中最先进的靶点，但另外还有九种恶性疟原虫蛋白质也已与抑制剂一起结晶，这显然是一个发展非常迅速的领域。同时也将对基于结构的药物发现相对于已知抗疟药物的局限性进行一些探讨。
