Ragno Rino, Frasca Simona, Manetti Fabrizio, Brizzi Antonella, Massa Silvio
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via A. Moro, I-53100 Siena, Italy.
J Med Chem. 2005 Jan 13;48(1):200-12. doi: 10.1021/jm0493921.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), a definitive role in the treatment of HIV-1 infections. Since the appearance of HEPT and TIBO, more than 30 structurally different classes of compounds have been reported as NNRTIs, which are specific inhibitors of HIV-1 replication, targeting the HIV-1 reverse transcriptase (RT). Nevirapine and delavirdine are the first formally licensed for clinical use, and others have been licensed afterward, while several are in preclinical or clinical development. The NNRTIs interact with a specific site of HIV-1 RT (nonnucleoside binding site, NNBS) that is close to, but distinct from, the NRTI binding site. In this work we report the application of the Autodock program assessing its usability through reproduction of 41 NNRTI experimental bound conformations. Moreover, cross-docking experiments on the wild-type and mutated RT forms were conducted to take into account the enzyme flexibility as a valuable tool for structure-based drug design (SBDD) studies and to gain insight on the mode of action of new anti-HIV agents active against both wild-type and resistant strains.
除核苷类逆转录酶抑制剂（NRTIs）和蛋白酶抑制剂（PIs）外，非核苷类逆转录酶抑制剂（NNRTIs）在治疗HIV-1感染中也具有明确作用。自HEPT和TIBO出现以来，已有超过30种结构不同的化合物类别被报道为NNRTIs，它们是HIV-1复制的特异性抑制剂，作用靶点为HIV-1逆转录酶（RT）。奈韦拉平和地拉韦定是首批正式获批用于临床的药物，之后又有其他药物获批，同时还有几种药物正处于临床前或临床开发阶段。NNRTIs与HIV-1 RT的一个特定位点（非核苷结合位点，NNBS）相互作用，该位点靠近但不同于NRTI结合位点。在这项工作中，我们报告了Autodock程序的应用，通过重现41种NNRTI实验结合构象来评估其可用性。此外，还对野生型和突变型RT形式进行了交叉对接实验，以将酶的灵活性作为基于结构的药物设计（SBDD）研究的一个有价值工具，并深入了解对野生型和耐药菌株均有活性的新型抗HIV药物的作用模式。
