手性拓扑电荷指数和构效关系研究

对拓扑电荷指数进行了扩展,得到了含电负性的手性拓扑电荷指数。将其与Julián-Qrtiz 等人对该指数的扩展结果相比较,结果表明,新的拓扑指数能够得到更好的QSAR 模型。进一步运用人工神经网络法构造了数学模型,该模型能够更好地预测手性化合物的活性。     

QSAR技术对化妆品中防晒剂成分经皮暴露评估

将国外先进的计算机模拟预测技术应用于化妆品安全性评价中,进行防晒剂成分的经皮暴露评估。采用国外先进的QSAR（Quantitative Structure Activity Relationship）测试模块,对防晒剂成分的经皮吸收特性进行了计算和评价。同时对防晒剂成分的皮肤接触过敏性、人体感觉刺激性以及眼刺激性分别进行了预测和评价。结果表明,防晒剂成分的经皮吸收性质差异较大,经皮吸收剂量DAD值在0．0407～12672mg／kg／day之间。其中苯基苯并眯唑磺酸和二苯酮-5的经皮吸收量较小,分别为0．0769和0．0407mg／kg／day,奥克立林、甲氧基肉桂酸辛酯和水杨酸乙基己酯的经皮吸收量很大,分别为12672、1843和2136．1mg／kg／day。另外防晒剂成分表现出不同的皮肤接触过敏性、人体感觉刺激性以及眼刺激性可能性,尤其是二苯酮-3和苯基苯并咪唑磺酸作为防晒剂成分,其过敏性和刺激性可能性较高,而4-二甲氨基苯甲酸2-乙基己酯可能性较低。可得结论：化妆品中物质的辛醇／水分配系数（Kow）和化学物分子质量（MW）不同将导致物质经皮吸收系数（Kp）不同,从而对物质经皮吸收特性产生影响,进而对化妆品产品的安全性和功效性产生影响。同时防晒剂成分应用于化妆品产品中时,对人体可能有一定的皮肤接触过敏性、人体感觉刺激性以及眼刺激性作用,提示其有一定的人体暴露风险,需要引起注意。先进的QSAR技术应用于化妆品安全性和功效性评价中,将推动毒理学领域替代技术的研究和发展。     

计算机技术在有机氟农药构效关系研究中的应用

本文着重于探讨计算机技术在构效关系研究中的应用，首先利用分子结构片段法提取农药的特征参数，然后引入神经网络技术对其构效关系进行研究，最终获得一个具有较好的预测网络，可用于对有机氟农药的结构进行预测筛选，对加快农药的开发和研制具有重大意义。     

Stereochemical and steric control of the UDP-glucuronosyltransferase-catalyzed conjugation reaction: a rational approach for the design of inhibitors for the human UGT2B7

A set of 76 derivatives of the epimeric tricyclic sesquiterpenols longifolol and isolongifolol was subjected to inhibition and glucuronidation assays employing the human UDP-glucuronosyltransferase (UGT) 2B7. Detailed structure-activity relationships (SARs) with respect to functionality, stereochemical properties, and steric features were derived. To gain further insight into the SARs of UGT2B7 ligands herein, we have developed a 3D-quantitative structure-activity relationship (3D-QSAR) using Comparative Molecular Similarity Analysis (CoMSIA). The formation of the enzyme-inhibitor complex was predominantly controlled by spatially directed hydrophobic interactions. The glucuronidation rate was significantly influenced by the steric demand of substituents in proximity of the nucleophilic hydroxy group. The glucuronidation of the compounds was prevented by the introduction of bulky substituents such as isopropyl, tert-butyl, and phenyl groups. The epimeric longifolol derivatives of series D were the best inhibitors displaying IC(50) values as low as 4.6 nM. This study shows that high-potency substrates can be turned into potent inhibitors by addressing functional, stereochemical, and steric properties.     

Design of novel camphane-based derivatives with antimycobacterial activity

Although tuberculosis (TB) continues to be one of the leading infectious disease killers globally, it is curable and preventable. Despite the existence of safe, well tolerated and effective drugs used in the TB treatment, the interest in new entities, combinations and regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB agents – camphane-based derivatives with nanomolar activity against Mycobacterium tuberculosis strains. The quantitative structure–activity relationship (QSAR) study on 12 compounds revealed several structural requirements for antimycobacterial activity: two hydrogen bond donors, two or three rings and no large branched substituents. Here, we describe the design of a set of nine novel camphane-based derivatives following these requirements. The compounds were synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities in the nanomolar range, significantly higher than the activities in the initial set. The QSAR study based on all 21 derivatives pointed to two main structural requirements for anti-TB activity: two hydrogen bond donors and a side chain with aromatic ring.     

In silico screening and study of novel ERK2 inhibitors using 3D QSAR,docking and molecular dynamics

ERK2 is a dual specificity protein kinase, part of the Ras/Raf/MEK/ERK signal transduction cascade. It forms an interesting target for inhibition based on its relationship with cell proliferation and oncogenesis. A 3D QSAR pharmacophore model (Hypo1) with high correlation (r = 0.938) was developed for ERK2 ATP site on the basis of experimentally known inhibitors. The model included three hydrogen bonds, and one hydrophobic site. Assessment of Hypo1 through Fisher randomization, cost analysis, leave one out method and decoy test suggested that the model can reliably detect ERK2 inhibitors. Hypo1 has been used for virtual screening of potential inhibitors from ZINC, Drug Bank, NCI, Maybridge and Chembank databases. Using Hypo1 as a query, databases have been interrogated for compounds who meet the pharmacophore features. The resulting hit compounds were subject to docking and analysis. Docking and molecular dynamics analysis showed that in order to achieve a higher potency compounds have to interact with catalytic site, glycine rich loop, Hinge region, Gatekeeper region and ATP site entrance residues. We also identified catalytic site and Glycine rich loop as important regions to bind by molecules for better potency and selectivity.     

Modeling structure–activity relationships of prodiginines with antimalarial activity using GA/MLR and OPS/PLS

In the present study, we performed a multivariate quantitative structure-activity relationship (QSAR) analysis of 52 prodiginines with antimalarial activity. Variable selection was based on the genetic algorithm (GA) and ordered predictor selection (OPS) approaches, and the models were built using the multiple linear regression (MLR) and partial least squares (PLS) regression methods. The leave-N-out crossvalidation and y-randomization tests showed that the models were robust and free from chance correlation. The mechanistic interpretation of the results was supported by earlier findings. In addition, the comparison of our models with those previously described indicated that the OPS/PLS-based model had a higher quality of external prediction. Thus, this study provides a comprehensive approach to the evaluation of the antimalarial activity of prodiginines, which may be used as a support tool in designing new therapeutic agents for malaria.