淋病奈瑟菌已经逐渐对几乎所有的抗生素产生耐药性,因此,必须开发新的方法来对抗其多重耐药性。MtrCDE的过表达,RND家族外排泵,是淋球菌中抗生素耐药性的主要原因之一,被认为是对抗抗微生物耐药性的重要目标。PaβN,D13-9001和其他EPI被确定为针对RND外排泵,但是由于它们的细胞毒性,他们在临床试验中失败了。在这里,我们进行了广泛的基于药效团的方法,以鉴定药理学/安全性改善的新型EPI抑制剂.包含药效团生成的集成计算框架,使用HTVS进行虚拟筛选,SP和XPGlide方法,MM-GBSA分析,诱导配合对接,QPLD,DFT,ADMET属性计算,分子动力学,并进行MM-PBSA分析。全面的研究导致五个无毒的生物活性化合物的鉴定,即-ZINC000008764610,ZINC000030879142,ZINC000030879358,ZINC000253414904和ZINC000225394671,作为淋球菌RND外排泵的潜在EPI。这五个化合物是根据药效基团作图选择的,比已知的EPI更高的码头得分,结合稳定性,与MtrD蛋白关键残基的分子相互作用,更高的ADMET属性,无毒性,和自由能估计。总之,该分析导致从ZINC数据库的天然化合物亚组中鉴定出5个最高命中,这些亚组对MtrD具有更高的结合亲和力,并且具有足够的生理化学/药代动力学特征,可用于产生针对淋病奈瑟菌的新型EPI.
Neisseria gonorrhoeae have progressively developed resistance to almost all antibiotics, and it has become imperative to develop novel approaches to combat its multi-drug resistance. Overexpression of the MtrCDE, an RND family efflux pump, is one of the primary causes of antibiotic resistance in the gonococcus and is considered an important target for combating anti-microbial resistance. PaβN, D13-9001, and other EPIs are identified to target the RND efflux pumps, but due to their cytotoxicity, they have failed in clinical trials. Herein, an extensive pharmacophore-based approach was performed to identify novel EPI inhibitors with improved pharmacology/safety profiles. An integrated computational framework comprising pharmacophore generation, virtual screening using HTVS, SP and XP Glide methodology, MM-GBSA analysis, Induced fit docking,
QPLD, DFT, ADMET properties calculation, Molecular Dynamics, and MM-PBSA analysis was performed. The comprehensive study leads to the identification of five non-toxic bioactive compounds, namely - ZINC000008764610, ZINC000030879142, ZINC000030879358, ZINC000253414904, and ZINC000225394671, as potential EPIs for RND efflux pump of Neisseria gonorrhoeae. The five compounds were selected based on the pharmacophore mapping, higher dock score than the known EPIs, binding stability, molecular interactions with the critical residues of MtrD protein, higher ADMET properties, non-toxicity, and free energy estimations. In summary, the analysis led to the identification of five top hits from the natural compound subset of the ZINC database that has a higher binding affinity to the MtrD and adequate physiochemical/pharmacokinetic profile that can be used for the generation of novel EPIs against Neisseria gonorrhoeae.