Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
Int J Mol Sci. 2018 Jun 23;19(7):1851. doi: 10.3390/ijms19071851.
Carbonic anhydrase II (CAII) is a zinc-containing metalloenzyme whose aberrant activity is associated with various diseases such as glaucoma, osteoporosis, and different types of tumors; therefore, the development of CAII inhibitors, which can represent promising therapeutic agents for the treatment of these pathologies, is a current topic in medicinal chemistry. Molecular docking is a commonly used tool in structure-based drug design of enzyme inhibitors. However, there is still a need for improving docking reliability, especially in terms of scoring functions, since the complex pattern of energetic contributions driving ligand⁻protein binding cannot be properly described by mathematical functions only including approximated energetic terms. Here we report a novel CAII-specific fingerprint-based (IFP) scoring function developed according to the ligand⁻protein interactions detected in the CAII-inhibitor co-crystal structures of the most potent CAII ligands. Our IFP scoring function outperformed the ability of Autodock4 scoring function to identify native-like docking poses of CAII inhibitors and thus allowed a considerable improvement of docking reliability. Moreover, the ligand⁻protein interaction fingerprints showed a useful application in the binding mode analysis of structurally diverse CAII ligands.
碳酸酐酶 II（CAII）是一种含锌的金属酶，其异常活性与各种疾病有关，如青光眼、骨质疏松症和不同类型的肿瘤；因此，开发 CAII 抑制剂是药物化学中的一个热门课题，CAII 抑制剂可能成为治疗这些疾病的有前途的治疗剂。分子对接是基于结构的酶抑制剂药物设计中常用的工具。然而，对接可靠性仍然需要提高，特别是在评分函数方面，因为仅包括近似能量项的数学函数无法正确描述驱动配体-蛋白结合的复杂能量贡献模式。在这里，我们报告了一种新的基于 CAII 特异性指纹（IFP）的评分函数，该函数是根据 CAII-抑制剂共晶结构中最有效的 CAII 配体检测到的配体-蛋白相互作用开发的。我们的 IFP 评分函数优于 Autodock4 评分函数识别 CAII 抑制剂天然样对接构象的能力，从而大大提高了对接可靠性。此外，配体-蛋白相互作用指纹在结构多样的 CAII 配体的结合模式分析中具有有用的应用。
