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从分子动力学模拟探讨 GRL-98065 抑制剂与 HIV-1 蛋白酶野生型及 I50V V82A 和 I84V 突变体结合和耐药的机制。

Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations.

机构信息

College of Physics and Electronics, Shandong Normal University, 88 Wenhua East Road, Jinan 250014, PR China.

出版信息

Eur J Med Chem. 2010 Jan;45(1):227-35. doi: 10.1016/j.ejmech.2009.09.048. Epub 2009 Oct 13.

DOI:10.1016/j.ejmech.2009.09.048
PMID:19910081
Abstract

The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor-protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT.

摘要

单突变 I50V、V82A 和 I84V 被认为是 HIV-1 蛋白酶耐药性的关键残基突变。使用 MM-PBSA 方法计算的绝对结合自由能的排名与实验结果非常吻合。分析焓和熵平衡，以解释 I50V 和 V82A 的耐药性，它们的熵贡献比野生型（WT）复合物高。范德华能的降低解释了 I84V 对 GRL-98065 的耐药性。计算 GRL-98065 与单个蛋白质残基之间的详细结合自由能，以深入了解抑制剂-蛋白质结合和耐药机制。我们的结果表明，与 WT 相比，I50V 和 V82A 的结构变化比 I84V 大。

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