COMPUTER MODELING AND DRUG DESIGN

计算核心的广泛目标是支持该计划项目的细胞生物学，分子生物学，生物化学，晶体学和药物化学组成部分，以治疗恰加斯病，疟疾，非洲昏睡病和利什曼病。靶点分别是克氏锥虫、恶性疟原虫、布氏锥虫和硕大利什曼原虫中的半胱氨酸蛋白酶。生物信息学、比较蛋白质结构建模和计算对接将有助于靶标发现、先导物发现和先导物优化。特别是，计算将应用于发现潜在的目标半胱氨酸蛋白酶，其蛋白质抑制剂和药物样化合物。具体目标是： (i)鉴定T. cruzi、恶性疟原虫、布氏锥虫和L.少校， (ii)鉴定靶半胱氨酸蛋白酶的所有推定的蛋白质抑制剂; (iii)提出适合作为药物开发的先导化合物的小抑制剂， 寄生虫半胱氨酸蛋白酶; (iv)以支持针对少量蛋白酶靶标（包括cruzein、rhodesain和falcipains 2和3）的少量先导物的先导物优化的迭代过程。 所提出的计算是及时的，由于基因组序列，蛋白质结构，计算能力的可用性之间的汇合，以及蛋白质序列，蛋白质结构建模和配体对接的比较方法的进步。

The broad goal of the computational core is to support the cell biology, molecular biology, biochemistry, crystallography, and medicinal chemistry components of the program project towards cures for Chagas' disease, malaria, African sleeping sickness, and leishmaniasis. The targets are cysteine proteases in Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, and Leishmania major, respectively. Bioinformatics, comparative protein structure modeling, and computational docking will contribute to target discovery, lead discovery, and lead optimization. In particular, computing will be applied to the discovery of potential target cysteine proteases, their protein inhibitors, and drug-like compounds. The specific aims are: (i) to identify all putative papain-like cysteine proteases in the genomes of T. cruzi, P. falciparum, T.brucei, and L. major, (ii) to identify all putative protein inhibitors of the target cysteine proteases; (iii) to suggest small inhibitors that are suitable as lead compounds for drug development against parasite cysteine proteases; (iv) to support the iterative process of lead optimization for a small number of leads against a small number of protease targets, including cruzein, rhodesain, and falcipains 2 and 3. The proposed computations are timely due to the confluence between the availability of the genomic sequences, protein structures, computing capabilities, and advances in methods for comparison of protein sequences, protein structure modeling, and ligand docking.