分子构效关系研究的模式识别方法

定量构效关系 QSAR是研究并揭示物质结构和活性之间的联系 ,近年来有广泛的研究与应用。在一定程度上 ,联系揭示的是一种模式识别的问题 ,本文介绍了在此类研究中所涉及到的模式识别方法 ,并作了一些前景展望     

化合物构效关系的模糊极小极大神经网络识别研究

应用模糊极小极大神经网络研究了化合物复杂结构和性能（QSAR）之间的关系，用该法进行几组化合物致癌的识别，结果优于线性回归的方法，对此作出一些分析。     

Contraluminal transport of organic cations in the proximal tubule of the rat kidney

In order to study the quantitative structure/activity relationship of organic cation transport across the contraluminal side of the proximal renal tubule cell, the stopped-flow capillary microperfusion method was applied and the inhibitory potency (apparent K _i values) of different homologous series of substrates against N ¹-[³H]methylnicotinamide (NMeN⁺) transport was evaluated. Aniline and its ring- or N-substituted analogues as well as the aminonaphthalines do not interact with the contraluminal NMeN⁺ transporter except for the quaternary trimethylphenylammonium and pararosaniline, which bear a permanent positive charge, and for 1,8-bis-(dimethylamino)naphthaline, which forms an intramolecular hydrogen bond. If, however, one or more than one methylene group is interposed between the benzene ring and the amino group, the compounds interact with the contraluminal NMeN⁺ transporter in proportion to their hydrophobicity parameter, i.e. the octanol/water partition coefficient (log octanol). The catecholamines and other hydroxyl-substituted phenylethyl analogues also follow this rule. In addition, the N-heterocyclic pyridine, quinoline, isoquinoline and acridine analogues also interact with the contraluminal NMeN⁺ transporter, when their pK _a values are higher than 5.0, and, an inverse correlation between pK _a and log K _{i, NMeN} was observed. An exception to this rule are those hydroxy compounds of pyridine, quinoline and isoquinoline that show tautomerism. These compounds slightly inhibit NMeN⁺ transport despite low pK _a values. The quaternary nitrogen compounds of aniline and the N-heterocyclic analogues, as far as tested, all interact with the contraluminal NMeN⁺ transporter in relation to their hydrophobicity. The data indicate that the contraluminal NMeN⁺ transporter interacts with N-compounds according to their hydrophobicity and/or according to their basicity (affinity to protons). The reason for deviation of the aniline analogues and the OH-tautomeric heterocyclic N-compounds from this behaviour is discussed.     

Influence of substrate structure on substrate binding to the renal organic cation/H+ exchanger

 The carrier-mediated exchange of H⁺ for organic cations (”OC/H⁺ exchange”) is the active step in OC secretion in renal proximal tubules. Although hydrophobicity is known to be an important criterion for binding of substrates to this transporter, the degree to which steric parameters of substrate structure influence binding to the exchanger is unclear. We examined this issue by measuring the inhibition of OC/H⁺ exchange produced by a group of quaternary ammonium compounds which share a common structural motif: an N ¹-pyridinium residue. Activity of the OC/H⁺ exchanger was determined by measuring transport of [¹⁴C]tetraethylammonium (TEA) in brush-border membrane vesicles (BBMV) from rabbit renal cortex. Transport was measured in the presence of a pH gradient (pH_in 6.0; pH_out 7.5) to maximize TEA/H⁺ exchange. Apparent inhibitory constants (K _i values) for each test agent were measured. The test agents included 4-phenylpyridiniums and 3-phenylpyridiniums, quinoliniums and acridiniums. The planar structure of these compounds permits a direct test of whether the presence of planar hydrophobic mass in different orientations relative to the pyridinium motif exerts a systematic effect on substrate binding to the OC/H⁺ exchanger. The hydrophobicity of each group of compounds was systematically varied by addition of different substituents at the quaternary nitrogen. Whereas decreases in K _i proved to be proportional to hydrophobicity, the position of the phenyl-ring substituent(s) had no effect on substrate interaction with the exchanger. The results led to the development of a preliminary quantitative structure–activity relationship (QSAR) correlating substrate hydrophobicity and substrate binding to the OC/H⁺ exchanger. This QSAR was used to predict the binding of 1-methyl-4-phenylpyridinium (MPP⁺), (+) and (–)nicotine, (+) and (–)ephedrine, quinine and quinidine to the OC/H⁺ exchanger. Molecular graphics representation of the 3D structures of the test agents was used to develop a working model of a hydrophobic, planar receptor surface on the OC/H⁺ exchanger against which substrates are suggested to interact during binding. Development of the QSAR and receptor surface model open the way to quantitative tests of the specific physical and structural determinants of substrate selectivity by the renal OC/H⁺ exchanger. Received: 20 July 1998 / Received after revision and accepted: 19 October 1998     

Synthesis and Quantitative Structure‐activity Relationships Study for Arylpropenamide Derivatives as Inhibitors of Hepatitis B Virus Replication

A series of new arylpropenamide derivatives containing different aryl groups were synthesized, characterized, and evaluated for their anti‐hepatitis B virus (HBV) activities. A new high accuracy QSAR model of arylpropenamide was constructed based on a more completely activities data and calculation parameter. The 2D‐QSAR equations, by using DFT and multiple linear regression analysis methods, revealed that higher value of thermal energy (TE) and lower entropy (S^?) increase the anti‐HBV activities of the arylpropenamide molecules. Predictive 3D‐QSAR models were established by SYBYL multifit molecular alignment rule. The optimum models were all statistically significant with cross‐validated and conventional coefficients, indicating that they were reliable enough for activity prediction.     

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.     

三嗪类化合物对小鼠成淋巴细胞瘤离体二氢叶酸还原酶活性和对瘤细胞生长抑制作用的定量相关关系

三嗪类化合物对瘤细胞生长的抑制作用,和对自瘤细胞分离的二氢叶酸还原酶活性的抑制作用的差异,经多重回归分析建立的模型表明,与化合物的克分子折射呈负性相关。瘤组织酶与正常酶活性的抑制作用呈平行关系。