Structure-based design of potent inhibitors of scytalone dehydratase: Displacement of a water molecule from the active site
Structure-based design of potent inhibitors of scytalone dehydratase: Displacement of a water molecule from the active site
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DOI：
10.1021/bi981848r
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发表时间：
1998-12-22
期刊：
影响因子：
2.9
通讯作者：
Jordan, DB
中科院分区：
文献类型：
--
作者：
Chen, JM;Xu, SL;Jordan, DB
Scytalone脱氢酶（SD）是旨在保护水稻植物免受稻瘟病菌引起的真菌病害的抑制剂设计努力的分子靶标。如从SD-抑制剂复合物的X-射线衍射数据所确定的[Lundqvist等人（1994）Structure（伦敦）2，937-944]，在蛋白质侧链、抑制剂、和两个束缚水分子从SD复合喹唑啉和苯并三嗪抑制剂的模型，设计了一类新的有效的SD抑制剂，涉及活性位点的水分子的置换。我们能够通过合成具有腈官能度的化合物来增加抑制效力，该腈官能度显示在其中一个结晶水分子所占据的空间中。比较了16种抑制剂。有效的喹唑啉和苯并三嗪抑制剂向氰基喹啉和氰基喹啉的净转化使结合效力增加2-20倍。用氢原子取代腈使结合亲和力降低100-30000倍。SD-抑制剂复合物在1.65埃分辨率下的X射线晶体学数据证实，腈官能团如预期的那样置换了水分子，并且用酪氨酸30和50产生了有利的取向，酪氨酸30和50是与水分子的氢键网络的一部分。本文提供的抑制剂的其他数据揭示了两个氢键网络对抑制效力的重要性：一个在Asn 131和适当定位的抑制剂杂原子之间，一个在结合水分子和第二个抑制剂杂原子之间。
Scytalone dehydratase (SD) is a molecular target of inhibitor design efforts aimed at protecting rice plants from the fungal disease caused by Magnaporthe grisea, As determined from X-ray diffraction data of an SD-inhibitor complex [Lundqvist et al. (1994) Structure (London) 2, 937-944], there is an extended hydrogen-bonding network between protein side chains, the inhibitor, and two bound water molecules. From models of SD complexed to quinazoline and benztriazine inhibitors, a new class of potent SD inhibitors involving the displacement of an active-site water molecule were designed. We were able to increase inhibitory potency by synthesizing compounds with a nitrile functionality displayed into the space occupied by one of the crystallographic water molecules. Sixteen inhibitors are compared. The net conversion of potent quinazoline and benztriazine inhibitors to cyanoquinolines and cyanocinnolines increased binding potency 2-20-fold. Replacement of the nitrile with a hydrogen atom lowered binding affinity 100-30000-fold. X-ray crystallographic data at 1.65 Angstrom resolution on a SD-inhibitor complex confirmed that the nitrile functionality displaced the water molecule as intended and that a favorable orientation was created with tyrosines 30 and 50 which had been part of the hydrogen-bonding network with the water molecule. Additional data on inhibitors presented herein reveals the importance of two hydrogen-bonding networks toward inhibitory potency: one between Asn131 and an appropriately positioned inhibitor heteroatom and one between a bound water molecule and a second inhibitor heteroatom.