Allaka Tejeswara Rao, Katari Naresh Kumar, Veeramreddy Venkataramireddy, Anireddy Jaya Shree
Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500 085, India.
Department of Chemistry, GITAM School of Technology, GITAM University, HTP Campus, Rudraram, Medak, Telangana 502 329, India.
Curr Drug Discov Technol. 2018;15(2):109-122. doi: 10.2174/1570163814666170829142044.
Fluoroquinolones have been the centre of considerable scientific and clinical interest due to their broad spectrum pharmacological activities. Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections, and urinary tract infections. Hydrazone as a pharmacophore unit that attracts the medicinal chemists because of structure activity relationship (SAR) studies of fluoroquinolones especially the functionality at C-3 position. Consequently, recognition and development of potential ligands specifically for a protein target forms the primary goal in drug discovery process. Among the different theoretical approaches available, Gold and Glide are the molecular docking methods which find application protein ligand studies. In the current study, the DNA gyrase of Staphylococcus aureus has been used as the target protein to understand their possible interactions.
The crystal structure of DNA gyrase (topoisomerase II) was downloaded from the Protein Data Bank (PDB ID: 2XCS, 3FOE) and molecular docking studies were performed using the docking programs like Gold 3.2 (Genetic Algorithm for Ligand Docking), Glide 5.0 (Grid Based Ligand Docking with Energetic). Melting points were uncorrected and determined in open capillary tubes in a melting point apparatus. TLC was performed on silica gel-G and spotting was done using iodine/ KMnO4 staining or UV-light. The following experimental procedures are representive of the general procedures used to synthesize all compounds.
The docking experiments of the title compounds with 2.1 Å crystal structure of DNA gyrase 2XCS, 3FOE using Gold 3.2 and Glide 5.0 is carried out to understand the binding interactions of the novel ligands with the protein, contributing for antibacterial activity. The compounds in general exhibited good binding interactions like H-bonding interaction and π-π interactions which stabilize the protein-ligand complexes and responsible for good fitness scores in both the protocols.
In summary, a new series of novel pefloxacin hydrazones 5a-5n were studied for their interactions with Staphylococcus aureus DNA gyrase protein by Glide 5.0 and Gold 3.2 molecular docking protocols [PDB IDS: 2XCS, 3FOE]. Among the tested molecules, compound 5g exhibited a good Glide score value of - 7.73 and Glide energy -51.24 with emodel value of -66.16. The nice docking scores of 5g, 5a, 8h, 5m and 5b revealed that these compounds are well accommodated on the active site residues of DNA gyrase enzyme. From the docking study, we have explored the probable binding mode and the binding pattern of compounds 5f, 5l, 5h, 5d, and 5n showed that they strongly interact with in the active site of Staphylococcus aureus of DNA gyrase enzyme. From screening results it is found that compounds having aromatic ring substituted with electron releasing groups are showing potent docking scores and exhibited better fitness than reference compounds CPF and CA4. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the pefloxacin derivatives.
氟喹诺酮类药物因其广泛的药理活性而成为大量科学研究和临床关注的焦点。培氟沙星是诺氟沙星的类似物，诺氟沙星是第三代氟喹诺酮类抗生素，与环丙沙星类似。培氟沙星用于治疗多种细菌感染，如呼吸道感染、耳鼻喉（ENT）感染、皮肤感染和尿路感染。腙作为一种药效基团单元，由于氟喹诺酮类药物的构效关系（SAR）研究，特别是C-3位的官能团，吸引了药物化学家的关注。因此，识别和开发针对特定蛋白质靶点的潜在配体是药物发现过程中的主要目标。在现有的不同理论方法中，Gold和Glide是用于蛋白质-配体研究的分子对接方法。在本研究中，金黄色葡萄球菌的DNA回旋酶被用作靶蛋白以了解它们可能的相互作用。
从蛋白质数据库（PDB ID：2XCS，3FOE）下载DNA回旋酶（拓扑异构酶II）的晶体结构，并使用Gold 3.2（配体对接遗传算法）、Glide 5.0（基于网格的带能量的配体对接）等对接程序进行分子对接研究。熔点未校正，在熔点仪的开口毛细管中测定。TLC在硅胶-G上进行，使用碘/高锰酸钾染色或紫外光进行斑点检测。以下实验步骤代表了用于合成所有化合物的一般步骤。
使用Gold 3.2和Glide 5.0对标题化合物与DNA回旋酶2XCS、3FOE的2.1 Å晶体结构进行对接实验，以了解新型配体与蛋白质的结合相互作用，这有助于抗菌活性。这些化合物总体上表现出良好的结合相互作用，如氢键相互作用和π-π相互作用，这些相互作用稳定了蛋白质-配体复合物，并在两种方案中都给出了良好的拟合分数。
总之，通过Glide 5.0和Gold 3.2分子对接程序[PDB ID：2XCS，3FOE]研究了一系列新的培氟沙星腙5a - 5n与金黄色葡萄球菌DNA回旋酶蛋白的相互作用。在测试的分子中，化合物5g表现出良好的Glide评分值-7.73和Glide能量-51.24，e模型值为-66.16。5g、5a、8h、5m和5b的良好对接分数表明这些化合物很好地容纳在DNA回旋酶的活性位点残基上。从对接研究中，我们探索了化合物5f、5l、5h、5d和5n的可能结合模式和结合方式，结果表明它们与金黄色葡萄球菌DNA回旋酶的活性位点有强烈相互作用。从筛选结果发现，具有被供电子基团取代的芳环的化合物显示出有效的对接分数，并且比参考化合物CPF和CA4表现出更好的拟合度。分子建模和生物活性的有效结合为QSAR指导方针提供了见解，这有助于培氟沙星衍生物的进一步开发和优化。
