Miranda Williams E, Ngo Van A, Valiente Pedro A, Noskov Sergei Yu
Computational Biology and Biomolecular Dynamics Laboratory, Center for Protein Studies, Faculty of Biology, University of Havana , Havana, Cuba.
Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary , 2500 University Drive, BI-449, Calgary, Alberta T2N 1N4, Canada.
J Phys Chem B. 2016 Aug 18;120(32):7824-35. doi: 10.1021/acs.jpcb.6b05628. Epub 2016 Aug 4.
One of the essential challenges in the description of receptor-drug interactions in the presence of various polyvalent cations (such as zinc, magnesium, or iron) is the accurate assessment of the electronic effects due to cofactor binding. The effects can range from partial electronic polarization of the proximal atoms in a receptor and bound substrate to long-range effects related to partial charge transfer and electronic delocalization effects between the cofactor and the drug. Here, we examine the role of the explicit account for electronic effects for a panel of small-molecule inhibitors binding to the zinc-aminopeptidase PfA-M1, an essential target for antimalarial drug development. Our study on PfA-M1:inhibitor interactions at the QM level reveals that the partial charge and proton transfer due to bound zinc ion are important mechanisms in the inhibitors' recognition and catalysis. The combination of classical MD simulations with a posteriori QM/MM corrections with novel DFTB parameters for the zinc cation and the linear-interaction energy (LIE) approach offers by far the most accurate estimates for the PfA-M1:inhibitor binding affinities, opening the door for future inhibitor design.
在描述存在各种多价阳离子（如锌、镁或铁）时受体与药物的相互作用方面，一个至关重要的挑战是准确评估辅因子结合所产生的电子效应。这些效应的范围可以从受体和结合底物中近端原子的部分电子极化，到与辅因子和药物之间部分电荷转移及电子离域效应相关的远程效应。在此，我们研究了明确考虑电子效应对于一组与锌氨肽酶PfA-M1结合的小分子抑制剂的作用，PfA-M1是抗疟药物开发的一个重要靶点。我们在量子力学（QM）水平上对PfA-M1与抑制剂相互作用的研究表明，结合的锌离子引起的部分电荷和质子转移是抑制剂识别和催化过程中的重要机制。经典分子动力学（MD）模拟与基于新的锌阳离子密度泛函紧束缚（DFTB）参数的后验QM/MM校正以及线性相互作用能（LIE）方法相结合，为PfA-M1与抑制剂的结合亲和力提供了迄今为止最准确的估计，为未来的抑制剂设计打开了大门。
