一种改进的遗传算法及其在喜树碱和三唑醇类化合物的QSAR研究中的应用

目的 :考察改进的遗传算法 (GA)在QSAR中的变量优选能力。方法 :用自编程的改进的GA选择变量 ,PLS方法拟合模型 ,对 7,9,10 ,11取代的喜树碱衍生物和取代苯环双三氮唑醇类抗真菌化合物两个数据组进行QSAR研究。结果 :对两个数据组分别得到了一批较常规QSAR分析结果更优的方程。结论 :GA作为一种启发式搜索算法以其高效快速、并行性的特点尤其适合于QSAR研究 ,但因其仅以统计指标为进化依据 ,故需对其实施必要的预处理及结果检查     

1-(取代萘基-2)-1,2-二氢-2,2-二甲基-4,6-二氨基-1,3,5-三嗪的合成及结构与抗癌活性的关系

按Modest方法合成了11个新的1-(取代萘基-2)-1,2-二氢-2,2-二甲基-4,6-二氨基-1,3,5-三嗪(Ⅴ)。用于合成三嗪的取代-2-萘胺(Ⅵ),也一并在本文中报道。以人早幼粒白血病细胞HL—60测定了(Ⅴ)的抗癌活性。定量构效关系研究表明,(Ⅴ)的抗癌活性与6-取代基的立体参数(MR)呈负相关关系。推测可能是刚性的萘环6-位取代基不为二氢叶酸还原酶的活性空间所容纳的缘故。     

Synthesis of 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Sixteen novel coumarin‐based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC₅₀ 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d , 5j , and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK‐293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π‐π interaction with Trp278. The tertiary amino group displayed significant cation‐π interaction with Phe329. The aromatic group showed π‐π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti‐Alzheimer agents.     

中药保健食品原料肝毒性预测研究

目的：开发一种更优的评估中药肝毒性的方法,为中药保健食品原料安全性评价提供参考。方法：基于国际公开构建肝毒性定量构效关系（QSAR）模型训练集数据,形成训练集。使用Discovery Studio 4.5对训练集进行主成分分析和聚类分析,针对每一类使用朴素贝叶斯（NB）、逻辑回归（LR）、邻近算法（KNN）等9种机器学习的方法构建QSAR模型,并利用交叉验证方法对模型构建方法进行评估。最后使用最优类模型对113种中药保健食品原料包含的783个成分进行了预测,根据多模型加权平均概率筛选出肝毒性成分占比较大的中药。结果：根据对训练集化合物的分析,可以看出第3类模型的准确率为85%～91%,高于现有报道的中药成分肝毒性预测模型。对中药保健食品原料成分的分析发现肝毒性化合物48个、不具有肝毒性的化合物735个,肝毒性预测概率为0.15～0.30,说明中药保健食品原料肝毒性普遍较低。预测肝毒性成分所占比例较高的中药有茜草、番泻叶、当归、大黄、丹参、厚朴、川芎、桑枝、桑白皮、五味子等。结论：对训练集预先聚类,提高QSAR模型准确率,为中药安全性评价的方法学研究提供了新思路,为中药保健食品原料成分进...     

喜树碱代谢活性产物SN-38类似物的抗肿瘤构效关系研究

目的:研究喜树碱代谢活性产物的抗肿瘤定量构效关系。方法:采用经典二维定量构效关系方法对代谢类似物的logP、拓扑性指数、电性参数和几何参数等16个参数进行研究。结果:获得相关性较好的定量构效关系方程(R2=0.85),表明喜树碱代谢活性产物的抗肿瘤活性与一阶价分子连接性指数、氮氧电荷绝对值、最大正电荷、零阶价分子连接性指数相关。结论:此模型能有效预测喜树碱代谢活性产物SN-38类似物的构效关系,并对新化合物的设计提供指导。     

Identifying de‐NEDDylation inhibitors: Virtual high‐throughput screens targeting SENP8

Protein modification can have far‐reaching effects. NEDDylation, a protein modification process with the protein NEDD8, stabilizes and modifies how the targeted protein interacts with other proteins. Its role in system regulation makes it a prime therapeutic target, and virtual high‐throughput screening has already identified new NEDD8 inhibitors. SENP8 matures the NEDD8 proenzyme into the active form and regulates NEDDylation by removing NEDD8 from over‐NEDDylated proteins. In this work, SENP8 inhibitor candidates were identified in two rounds of virtual high‐throughput screening. Of the ten candidates identified in the first round of screening, four were active in validation experiments to yield an experimental hit rate of 40%. Of the five candidates identified in the second round of screening, one was active in validation experiments to yield an experimental hit rate of 20%. Results indicate virtual high‐throughput screening improved hit rates over traditional high‐throughput screening. The SENP8 inhibitor candidates can be used to interrogate the NEDDylation regulation mechanism.     

QSAR of clinically important EGFR mutant L858R/T790M pyridinylimidazole inhibitors

EGFR is a well‐established therapeutic target of clinical relevance in cancer. However, acquisition of secondary mutation (T790M) makes first‐generation inhibitors ineffective. Therefore, to circumvent the problem of resistance, new T790M/L858R (TMLR) double mutant inhibitors are required. In this study, fragment‐based QSAR models (GQSAR) were generated for pyridinylimidazole derivatives having biological activity against TMLR mutants. The GQSAR model developed using partial least squares regression via stepwise forward–backward variable selection technique showed best results as judged using statistical parameters (r², q², and pred_r²). Additionally, applicability domain of the model was verified using Williams plot, which indicated that the predicted data are reliable. The GQSAR provided site‐specific clues wherein modifications related to decreasing lipophilic character and rotatable bonds and increasing SaaCHE‐index are required for improving inhibitory activity. Overall, the study indicated that the presence of acrylamide at R5 is essential for covalent bond formation with Cys797 and occurrence of aromatic residue at R2 is required for occupying hydrophobic region next to Met790 gatekeeper residue. Based on this information, new derivatives were designed that show better inhibitory activity than the experimentally reported most active molecules. Thus, the model developed can be used to design new pyridinylimidazole derivatives with improved TMLR bioactivity.     

探讨定量构效关系模型在药物及其杂质毒性预测方面的应用

随着定量构效关系（QSAR）模型从二维至多维的不断发展,它被越来越广泛地应用于各个领域,同时也为药品的监管提供了新的参考方案。QSAR模型对于杂质的毒性预测可应用于药品的研发和质量控制过程,有利于控制药品的安全风险,缩减企业的研发成本。QSAR模型的应用程序也在不断优化,以确保QSAR模型可以不断地适用于新药及未知杂质的毒性研究。本文从QSAR模型的建模基础及发展历程出发,对近年来该模型在药物及其杂质毒性预测方面的应用研究报道进行了归纳总结。     

In silico strategies on prion pathogenic conversion and inhibition from PrPC –PrPSc

Introduction: To date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrP^C, block the conversion of PrP^C-PrP^Sc and increased effect on PrP^Sc clearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood–brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo.

Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrP^C-PrP^Sc.

Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrP^res in cell culture, inhibit the aggregation of a PrP^C peptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds.