Mitku Melese Legesse, Simegn Wudneh, Chanie Gashaw Sisay, Mohammed Seid Abdulwase, Beyna Alemante Tafese, Kebad Mengesha Assefa, Melese Mihret, Esubalew Dereje, Gela Yibeltal Yismaw, Ayenew Wondim, Limenh Liknaw Workie
Department of Pharmaceutical Chemistry, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
Department of Social and Administrative Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
SAGE Open Med. 2024 Aug 27;12:20503121241271810. doi: 10.1177/20503121241271810. eCollection 2024.
The development of multidrug resistant strains of extended-spectrum β-lactamase-producing has become a global problem; therefore, the discovery of new antibacterial agents is the only available solution.
To improve and propose new compounds with antibacterial activity, the three-dimensional quantitative structure-activity relationship and molecular docking studies were carried out on Aztreonam analogs as inhibitors in DNA gyrase B.
This study's 3D-Quantitative structure-activity relationship model was created using on the Comparative Molecular Field Analysis and the Comparative Molecular Similarity Indices Analysis. Using the Comparative Molecular Field Analysis ( = 0.73; = 0.82), excellent predictability was achieved, and the best Comparative Molecular Similarity Indices Analysis model ( = 0.88; = 0.9). The generated model's ability to predict outcomes was assessed through external validation using a test set compound and an applicability domain technique. In this study, the steric, electrostatic, and hydrogen bond acceptor fields played a key role in antibacterial activity.
The results of the molecular docking revealed that the newly generated compound A6 has the highest binding affinity with DNA gyrase B. It forms 10 hydrogen bonds with amino acid residues of Asn104, Asn274, Asn132, Ser70, Ser237, Thr105, Glu273, and 2 salt bridges with amino acid residues of Ser70 and Glu273 and one pi-pi interacting with Gys271 amino acid residue in the binding site of 5G1, and this result was validated by a new assessment method. We created some novel, highly effective DNA gyrase B inhibitors based on the earlier findings, and the most accurate model predicted their inhibitory actions. The ADMET characteristics and pharmacological similarity of these novel inhibitors were also examined.
These findings would be very beneficial in guiding the optimization process for the identification of novel drugs that can address the issue of multiple drug resistance.
产超广谱β-内酰胺酶的多重耐药菌株的出现已成为一个全球性问题；因此，发现新的抗菌剂是唯一可行的解决方案。
为了改进并提出具有抗菌活性的新化合物，对作为DNA促旋酶B抑制剂的氨曲南类似物进行了三维定量构效关系和分子对接研究。
本研究的三维定量构效关系模型是使用比较分子场分析和比较分子相似性指数分析创建的。使用比较分子场分析（r2 = 0.73；q2 = 0.82），实现了出色的预测能力，以及最佳的比较分子相似性指数分析模型（r2 = 0.88；q2 = 0.9）。通过使用测试集化合物和适用域技术进行外部验证，评估了所生成模型预测结果的能力。在本研究中，空间、静电和氢键受体场在抗菌活性中起关键作用。
分子对接结果表明，新生成的化合物A6与DNA促旋酶B具有最高的结合亲和力。它与Asn104、Asn274、Asn132、Ser70、Ser237、Thr105、Glu273的氨基酸残基形成10个氢键，与Ser70和Glu273的氨基酸残基形成2个盐桥，并在5G1的结合位点与Gys271氨基酸残基形成一个π-π相互作用，并且该结果通过一种新的评估方法得到了验证。基于早期发现，我们创建了一些新型、高效的DNA促旋酶B抑制剂，并且最准确的模型预测了它们的抑制作用。还研究了这些新型抑制剂的ADMET特性和药理相似性。
这些发现对于指导优化过程以鉴定能够解决多重耐药问题的新型药物将非常有益。
