Virtual Screening in Structure-Based Drug Design for Malaria

疟疾仍然是当今世界最严重的健康问题之一，每年约有3亿人受影响，150万人死亡。造成这种疾病的最致命和最广泛的寄生虫是恶性疟原虫。由于寄生虫对传统药物的耐药性越来越强，迫切需要开发更有效的治疗方法。有两种方法是可行的：疫苗和新药。这两项措施对防治疟疾的蔓延和后果都可能是必要的。我们正在通过靶向一种对寄生虫生存至关重要的酶来解决这个问题。所有原生动物寄生虫都通过嘌呤碱基补救来制造嘌呤核苷酸（DNA和RNA的构建单元）。与人类不同，它们不能从简单的前体分子中制造嘌呤。补救途径中的关键酶是次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶（HGXPRT）。我们的计划是利用对HGXPRT精确结构的了解和计算机能力的增强来确定哪些化学物质能够紧密地特异性地结合到酶的活性位点上。然后，我们将测试这些化合物抑制纯化的人类和疟原虫酶的能力，以及它们抑制红细胞中疟原虫生长的能力。化学合成将用于提高这些化合物的有效性。

Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat the spread and consequences of malaria. We are approaching this problem by targeting an enzyme which is essential for the survival of the parasite. All protozoan parasites make their purine nucleotides (the building blocks of DNA and RNA) by purine base salvage. Unlike humans, they cannot make purines from simple precursor molecules. The key enzyme in the salvage pathway is hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). Our plan is to capitalize on knowledge of the precise structure of HGXPRT and the increased power of computers to determine which chemicals are able to bind tightly and specifically to the active site of the enzyme. We will then test the ability of these compounds to inhibit purified human and Plasmodium enzymes and their ability to inhibit the growth of the malarial parasite in red cells. Chemical synthesis will be used to improve the effectiveness of these compounds.