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3亿人受到影响，有记录的死亡人数为150万人。造成这种疾病的最致命和分布最广的寄生虫是恶性疟原虫。由于这种寄生虫对传统药物的抗药性越来越强，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。为了抗击疟疾的传播和后果，这两种方法可能都是必要的。我们正在通过靶向一种对寄生虫的生存至关重要的酶来解决这个问题。所有的原生动物寄生虫都通过回收嘌呤碱基来制造它们的嘌呤核苷酸(DNA和RNA的构建块)。与人类不同，它们不能从简单的前体分子中制造嘌呤。次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶(HGXPRT)是挽救途径中的关键酶。我们的计划是利用对HGXPRT精确结构的了解和计算机功能的增强来确定哪些化学物质能够紧密结合并特定地与酶的活性部位结合。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疾寄生虫生长的能力。将使用化学合成来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.