极性溶剂化和构型熵在设计针对HIV-1蛋白酶的抗逆转录病毒药物中的重要性,The Journal of Physical Chemistry B

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极性溶剂化和构型熵在设计针对HIV-1蛋白酶的抗逆转录病毒药物中的重要性
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2013-05-08 00:00:00 , DOI: 10.1021/jp3085292
Parimal Kar ₁ , Reinhard Lipowsky ₁ , Volker Knecht ₁

Affiliation

KNI-10033和KNI-10075都是亲和力在皮摩尔范围内的高亲和力临床前HIV-1蛋白酶（PR）抑制剂。在这项工作中，使用了分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法来研究这两种HIV-1 PR抑制剂对野生型和突变型蛋白酶的效价，前提是该效价与该蛋白的亲和力有关。药物为靶蛋白。结合自由能的分解揭示了结合亲和力或突变诱导的亲和力变化的起源。我们的计算表明，突变I50V引起了对这两种抑制剂的耐药性。另一方面，我们预测突变体I84V引起对KNI-10075的耐药性，而KNI-10033与野生型蛋白酶相比，对I84V突变体的作用更强。耐药性主要来自范德华相互作用和构型熵的不利变化。后者表明通常不宜在计算相对结合亲和力时忽略构型熵的变化。对于绑定的复杂PR_I50V–KNI-10075，增加的极性溶剂化自由能也有助于耐药性。将控制KNI-10033或KNI-10075与野生型蛋白酶结合的相互作用与抑制剂darunavir或GRL-06579A进行比较时，揭示了极性溶剂化自由能的重要性。尽管PR-KNI-10033或PR-KNI-10075的分子间静电和范德华相互作用以及溶剂化自由能的非极性成分的贡献比PR-DRV或PR-GRL-06579A更有利，但两者KNI-10033和KNI-10075与darunavir表现出相似的亲和力，而相对于GRL-06579A则具有较低的结合亲和力。这是因为极性溶剂化自由能相对于KNI-10033或KNI-10075较不适合darunavir或GRL-06579A。此处揭示的极性溶剂化的重要性突出表明，仅进行结构检查不足以确定药物结合中亲和力和亲和力变化的关键作用，但必须考虑溶剂化作用。对控制结合力和耐药性的分子力的详细了解可能有助于设计针对目前药物具有耐药性的针对HIV-1 PR变体的新型抑制剂。

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Importance of Polar Solvation and Configurational Entropy for Design of Antiretroviral Drugs Targeting HIV-1 Protease

Both KNI-10033 and KNI-10075 are high affinity preclinical HIV-1 protease (PR) inhibitors with affinities in the picomolar range. In this work, the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method has been used to investigate the potency of these two HIV-1 PR inhibitors against the wild-type and mutated proteases assuming that potency correlates with the affinity of the drugs for the target protein. The decomposition of the binding free energy reveals the origin of binding affinities or mutation-induced affinity changes. Our calculations indicate that the mutation I50V causes drug resistance against both inhibitors. On the other hand, we predict that the mutant I84V causes drug resistance against KNI-10075 while KNI-10033 is more potent against the I84V mutant compared to wild-type protease. Drug resistance arises mainly from unfavorable shifts in van der Waals interactions and configurational entropy. The latter indicates that neglecting changes in configurational entropy in the computation of relative binding affinities as often done is not appropriate in general. For the bound complex PR_I50V–KNI-10075, an increased polar solvation free energy also contributes to the drug resistance. The importance of polar solvation free energies is revealed when interactions governing the binding of KNI-10033 or KNI-10075 to the wild-type protease are compared to the inhibitors darunavir or GRL-06579A. Although the contributions from intermolecular electrostatic and van der Waals interactions as well as the nonpolar component of the solvation free energy are more favorable for PR–KNI-10033 or PR–KNI-10075 compared to PR–DRV or PR–GRL-06579A, both KNI-10033 and KNI-10075 show a similar affinity as darunavir and a lower binding affinity relative to GRL-06579A. This is because of the polar solvation free energy which is less unfavorable for darunavir or GRL-06579A relative to KNI-10033 or KNI-10075. The importance of the polar solvation as revealed here highlights that structural inspection alone is not sufficient for identifying the key contributions to binding affinities and affinity changes for the design of drugs but that solvation effects must be taken into account. A detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of new inhibitors against HIV-1 PR variants that are resistant against current drugs.

更新日期：2013-05-08

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