Amin Elizabeth A, Welsh William J
Department of Chemistry and Minnesota Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA.
J Chem Inf Model. 2006 Sep-Oct;46(5):2104-9. doi: 10.1021/ci0601362.
Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
基质金属蛋白酶（MMPs）因其在肿瘤转移以及诸如骨关节炎和类风湿性关节炎等退行性疾病的发生和扩散中所起的作用，一直是深入研究的对象。利用一系列具有高度预测性的三维定量构效关系模型，包括比较分子场分析和比较分子相似性指数分析，并结合对接和评分，在计算机上设计了一类初步的140种类药物小分子基质金属蛋白酶-3抑制剂，作为优化和合成的起始支架。选择沙利度胺作为构建新先导系列的骨架，因为它能适度抑制MMP-3，具有抗血管生成作用，并且易于进行结构修饰。大多数新化合物表现出中等至高的预测生物活性以及由正辛醇-水分配系数ClogP估计的良好生物利用度。特别是化合物102对MMP-3表现出极其有利的预测活性；具有适度的生物利用度；符合Lipinski的五规则；并且显示出作为潜在辅助抗癌或抗风湿治疗药物进行进一步优化、合成和实验评估的前景。
