Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Pabellòn 2 de Ciudad Universitaria, Ciudad de Buenos Aires C1428EHA, Argentina.
European Molecular Biology Laboratory - Hamburg Unit, Notkestrasse 85, Hamburg 22607, Germany.
J Chem Inf Model. 2022 Aug 8;62(15):3577-3588. doi: 10.1021/acs.jcim.2c00264. Epub 2022 Jul 19.
Protein-protein interactions (PPIs) are essential, and modulating their function through PPI-targeted drugs is an important research field. PPI sites are shallow protein surfaces readily accessible to the solvent, thus lacking a proper pocket to fit a drug, while their lack of endogenous ligands prevents drug design by chemical similarity. The development of PPI-blocking compounds is, therefore, a tough challenge. Mixed solvent molecular dynamics has been shown to reveal protein-ligand interaction hot spots in protein active sites by identifying solvent sites (SSs). Furthermore, our group has shown that SSs significantly improve protein-ligand docking. In the present work, we extend our analysis to PPI sites. In particular, we analyzed water, ethanol, and phenol-derived sites in terms of their capacity to predict protein-drug and protein-protein interactions. Subsequently, we show how this information can be incorporated to improve both protein-ligand and protein-protein docking. Finally, we highlight the presence of aromatic clusters as key elements of the corresponding interactions.
蛋白质-蛋白质相互作用（PPIs）是至关重要的，通过 PPI 靶向药物来调节其功能是一个重要的研究领域。PPI 位点是浅的蛋白质表面，容易被溶剂接近，因此缺乏合适的口袋来容纳药物，而它们缺乏内源性配体阻止了通过化学相似性进行药物设计。因此，开发 PPI 阻断化合物是一个艰巨的挑战。混合溶剂分子动力学已被证明可以通过识别溶剂位点（SSs）来揭示蛋白质活性位点中的蛋白质-配体相互作用热点。此外，我们的研究小组已经表明，SSs 可以显著提高蛋白质-配体对接的效果。在本工作中，我们将分析扩展到 PPI 位点。具体来说，我们分析了水、乙醇和苯酚衍生的 SSs 在预测蛋白质-药物和蛋白质-蛋白质相互作用方面的能力。随后，我们展示了如何将这些信息纳入其中，以改善蛋白质-配体和蛋白质-蛋白质对接的效果。最后，我们强调了芳香族簇作为相应相互作用的关键元素的存在。
