Khan Asad Ullah, Baig Mohd Hassan, Wadhwa Gulshan
Bioinformation. 2011 Jan 22;5(8):331-5. doi: 10.6026/97320630005331.
Extended-spectrum-β-lactamases (ESBLs), constitutes the growing class of betalactamses, these are enzymes produced by bacteria which impart resistance against advanced-generation-cephalosporins. SHV enzymes are among the most prevalent ESBLs. The mode of molecular interactions of recent SHV-variants to advanced generation cephalosporins has not been reported yet. This is the first time we are reporting the insilico study of these recent variants with new generation cephaosporins. Homology models for SHV-105, SHV-95, SHV-89, SHV-61 and SHV-48 were generated using MODELLER9v3. New generation Cephalosporins were selected to target the active site amino acid residues of these modeled SHV enzymes for predicting comparative efficacies of these inhibitors against the said enzymes on the basis of interaction energies of docking. The docked complexes were analyzed by using DISCOVERY STUDIO 2.5. In this study A237, S70, K234, R275, N132, R244 and S130 were found crucial to the correct positioning of drugs within the binding site of SHV enzymes in 11, 6, 6, 6, 5, 5 and 5 instances, respectively. On the basis of interaction energy and Ki calculations cefatoxime emerged as the most efficient among the other advanced cephalosporins against all the studied SHV variants, excluding SHV-48 where ceftazidime was found to be most effective drug. Furthermore, this study identified amino acid residues crucial to 'SHV-Cephalosporins' interactions and this information will be useful in designing effective and versatile drug candidates.
超广谱β-内酰胺酶（ESBLs）是不断增多的一类β-内酰胺酶，这些酶由细菌产生，可赋予对新一代头孢菌素的耐药性。SHV酶是最常见的ESBLs之一。目前尚未报道近期SHV变体与新一代头孢菌素的分子相互作用模式。这是我们首次报告对这些近期变体与新一代头孢菌素进行的计算机模拟研究。使用MODELLER9v3生成了SHV-105、SHV-95、SHV-89、SHV-61和SHV-48的同源模型。选择新一代头孢菌素靶向这些建模的SHV酶的活性位点氨基酸残基，以便根据对接的相互作用能预测这些抑制剂对所述酶的比较疗效。使用DISCOVERY STUDIO 2.5分析对接复合物。在本研究中，发现A237、S70、K234、R275、N132、R244和S130分别在11、6、6、6、5、5和5种情况下对于药物在SHV酶结合位点内的正确定位至关重要。基于相互作用能和Ki计算，头孢噻肟在所有其他新一代头孢菌素中对所有研究的SHV变体（不包括SHV-48，在SHV-48中发现头孢他啶是最有效的药物）是最有效的。此外，本研究确定了对“SHV-头孢菌素”相互作用至关重要的氨基酸残基，这些信息将有助于设计有效且通用的候选药物。
