DFT and GA Studies on the QSAR of 2-aryl-5-nitro-1 H -indole derivatives as NorA Efflux Pump Inhibitors

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• 作者：Yujie Dai ; Xu Zhang ; Xiuli Zhang ; Huanjie Wang and Zhansheng Lu
• 关键词：DFT ; Efflux pump inhibitor ; Genetic algrithum ; QSAR ; 2 ; aryl ; 5 ; nitro ; 1H ; indole
• 刊名：Journal of Molecular Modeling
• 出版年：2008
• 出版时间：September, 2008
• 年：2008
• 卷：14
• 期：9
• 页码：807-812
• 全文大小：132.7 KB

文摘

The structures of 2-aryl-5-nitro-1H-indole derivatives were optimized with PM3 and DFT at b3lyp/6–31 g* level successively. Some structural and electric descriptors were obtained from the single point energy calculation and natural bond orbital analysis at the level of b3lyp/6–31 g*. As efflux pump inhibitors, a QSAR model was built with genetic algrithum (GA) and partial least square (PLS) analyses. The high R 2 and R_\textCV\text2 R_{{\text{CV}}}^{\text{2}} indicates the derived model has a good predictive power which can be used in prediction of activity for new 2-aryl-5-nitro-1H-indole derivatives. This model gives us a revelation that the activity of 2-aryl-5-nitro-1H-indole derivatives as efflux pump inhibitor can be improved by properly increasing the molecular volume and Mulliken atomic charge of C₃ (Q _C3) or lowering the dipole and Mulliken atomic charge of C₄ (Q _C4) in 2-aryl and it was found from this article that a QSAR relationship can be built for small samples with large descriptors by compressing the descriptors with GA and analyzing with PLS. With this model, a new compound, 2-(2-Azidomethyl-5-phenoxy-phenyl)-5-nitro-1H-indole was predicted to lower the MIC of berberine to 0.091 μg/mL for inhibiting K2361 of S. aureus with NorA efflux pump protein over expression. Figure: Basic structure of 2-aryl-5-nitro-1H-indoles