Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors.

Competitive inhibitors of the salvage pathway enzyme purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) have been designed by using the three-dimensional structure of the enzyme as determined by x-ray crystallography. The process was an iterative one that utilized interactive computer graphics, Monte Carlo-based conformational searching, energy minimization, and x-ray crystallography. The proposed compounds were synthesized and tested by an in vitro assay. Among the compounds designed and synthesized are the most potent competitive inhibitors of purine nucleoside phosphorylase thus far reported. IMAGES:

研究人员借助X射线晶体学解析得到的酶三维结构，设计了补救途径（salvage pathway）酶嘌呤核苷磷酸化酶（purine-nucleoside phosphorylase，系统名：purine-nucleoside:orthophosphate ribosyltransferase，EC 2.4.2.1）的竞争性抑制剂。该设计流程为迭代式优化过程，采用了交互式计算机图形学、基于蒙特卡洛的构象搜索、能量最小化以及X射线晶体学技术。研究人员对所设计的候选化合物进行了合成，并通过体外实验（in vitro assay）开展活性测定。在所设计并合成的化合物中，包含了目前已报道的活性最强的嘌呤核苷磷酸化酶竞争性抑制剂。图片：