氨基酸描述子VHSEH用于多肽定量序效建模研究

从20 种天然氨基酸的171个物化性质出发, 按照疏水、立体和电性特征及氢键贡献将其分类后, 分别进行主成分分析, 得到一个新描述子VHSEH(Principal component score vector of hydrophobic, steric, electronic properties and, hydrogen bonds contributions). 对后叶催产素的结构进行了表征, 并以偏最小二乘法及D-优化划分样本建立了PLS定量序效关系模型, 得到复相关系数R2分别为 0.958 和 0.957, Q2分别为0.903和0.845, 约高于VHSE描述子模型值; 对抗菌肽进行了结构表征, 建立了PLS和OSC-PLS模型, 其R2分别为0.84和 0.995, Q2分别为0.546和0.926, 较SZOTT描述子结果好; 对58 个血管紧张素转化酶抑制剂进行QSAM研究, 得到R2, Q2及RMS分别为0.877, 0.838和0.361. 研究结果表明, VHSEH 描述子信息量大, 物化意义明确, 结果更易解释.     

基于氨基酸描述符SVHEHS的ACE抑制肽QSAR研究

收集20种天然氨基酸的457种理化性质,按照疏水、电性特征、氢键贡献和立体特征分类后,对它们分别进行主成分分析(Principal component analysis,PCA),得到一个新的氨基酸残基结构描述符SVHEHS.用该描述符分别对血管紧张素转化酶(AngiotensinⅠconverting enzyme,ACE)抑制二肽、三肽、四肽进行序列表征,并用来与生物活性建立偏最小二乘(Partial least square regression,PLS)模型.ACE抑制二肽、三肽、四肽模型的相关系数、交叉验证相关系数、 均方根误差、外部验证相关系数分别为0.607,0.507,0.587,0.783;0.852,0.813,0.232,0.839;1,1,0,0.935.由此说明,采用SVHEHS描述符建立的PLS模型拟合、预测能力均较好,可用于血管紧张素转化酶抑制肽的定量构效关系研究.     

一种新的三维氨基酸描述子及其在肽类药物QSAR中的应用

从20种天然氨基酸197个GETAWAY指数经主成分分析得出一种新3D氨基酸描述子——VSGETAWAY[vector of principal component scores for GETAWAY (geometry, topology and atom-weights assembly)]. 将其应用于48个苦味活性二肽、31个血管舒缓激肽促进剂和20个促凝血酶原激酶抑制剂结构表征并以偏最小二乘(PLS)对3个体系建立定量构效关系(QSAR)模型, 得复相关系数(Rcum2)与交互检验复相关系数(Qcum2)分别为0.887和0.753; 0.995和0.708; 0.999和0.802. 研究结果表明, VSGETAWAY描述子操作简便、结构表达能力强, 有望成为多肽药物QSAR研究中一种有效的结构表征方法.     

氨基酸结构描述子矢量VHSE及其在肽QSAR中的应用

从20种天然氨基酸的50个物化性质出发，按照疏水、立体和电性特征将其分类后分别进行主成分分析，并将产生的得分矢量即VHSE(principal component score vector of hydrophilicity,steric，and electronic properties)作为氨基酸结构描述子用于肽的定量构效关系研究。与已有方法相比，VHSE描述子具有物化意义明确、结果更易解释等特点。应用该描述子并结合逐步回归变量筛选和偏最小二乘建模方法，在对苦味二肽和血管舒缓激肽促进剂等体系的定量构效关系研究中，均取得了优于已有文献的结果。     

后叶催产素的定量构效关系研究

基于氨基酸物化性质的描述子矢量VHSE, 对21个后叶催产素类似物进行结构表征. 经逐步回归与偏最小二乘相结合的变量筛选技术, 根据模型的外部预测结果, 筛选得到一个最优的9变量组合. 应用该变量组合对21个后叶催产素类似物的促宫缩活性进行偏最小二乘建模, 模型复相关系数R2为92.6%, 留一法和留组法交互验证Q2分别为78.3%和79.4%. 结果表明, 后叶催产素的促宫缩活性主要与第3号氨基酸残基的疏水性、立体结构和电性性质以及第8号氨基酸残基的电性特征密切相关.     

一组新氨基酸描述子用于肽定量构效关系研究

用主成分分析从20种天然氨基酸0D～3D结构信息中收集到的共1369个描述子变量得到了一组新氨基酸描述子(SZOTT), 将其用于血管紧张素转化酶抑制剂和苦味二肽结构表征并以偏最小二乘法建立定量构效关系模型, 得复相关系数R_CU²分别为0.894和0.908, 留一法交互检验的复相关系数R_CV²分别为0.828和0.736, 估计均方根误差RMS分别为0.331和0.195. 研究结果表明, SZOTT描述子含信息量大, 操作简便, 结构表达能力强, 有望在多肽定量构效关系研究中得到进一步推广.     

Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and pi-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC(50) < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC(50) > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition.     

基于VHSE结构表征的TAP亲和活性预测及选择特异性分析

应用氨基酸描述子VHSE(Principal component score vector of hydrophobic, steric, and electronic properties)对613个抗原9肽进行结构表征, 在此基础上, 采用支持向量机结合逐步回归变量筛选方法, 成功建立了抗原肽抗原处理相关转运蛋白(Transporter associated with antigen processing, TAP)亲和活性预测模型, 最优线性支持向量机模型的R2, Q2和R2ext分别为0.7386, 0.7270和0.6057. 模型结果分析表明, 影响TAP亲和活性的首要因素是电性, 其次是立体和疏水性质; 底物9肽的P1(N端)及P2, P7和P9(C端)位氨基酸物化性质对TAP亲和活性有重要影响, 而P3, P4, P5和P6位对模型贡献相对较小, P8位则与活性无关. 依据最优模型对模拟点突变9肽的TAP亲和活性的预测结果, 并结合变量载荷分析, 对TAP底物选择特异性进行了分析和总结.     

Polymorphism of l‐Tryptophan

A new polymorph of l ‐tryptophan was prepared through crystallization from the gas phase, with structure determination carried out directly from powder XRD data augmented by periodic DFT‐D calculations. The new polymorph (denoted β) and the previously reported polymorph (denoted α) are both based on alternating hydrophilic and hydrophobic layers, but with substantially different hydrogen‐bonding arrangements. The β polymorph exhibits the energetically favourable l 2‐l 2 hydrogen‐bonding arrangement, which is unprecedented for amino acids with aromatic side chains. The specific molecular conformations adopted in the β polymorph facilitate this hydrogen‐bonding scheme while avoiding steric conflict of the side chains.     

基于VHSE结构表征的蛋白酶体酶切位点预测及酶切特异性研究

泛素-蛋白酶体在真核生物的抗原呈递、细胞周期调控和转录因子激活等生理过程中发挥着极为重要的作用,其核心就是蛋白酶体对底物的选择性酶切作用,因此对选择性酶切位点的预测一直是计算生物学的一个重点研究内容.针对现有酶切位点预测方法的非线性和物理意义不明确等问题,借鉴定量构效关系研究方法,采用基于氨基酸物理化学性质的描述子——VHSE(Principal component score vector of hydrophobic,steric,and electronic properties)对收集的2650个MHC-I配体的源蛋白序列进行了结构表征,在此基础上利用支持向量机建立了蛋白酶体酶切位点的预测模型,其最优线性模型的灵敏度(Sensitivity)、特异性(Specificity)、接受者操作特征曲线下面积(area under receiver operatingcharacteristics curve,AUC)和马休斯相关系数(Matthews coefficient of correlation,MCC)分别为90.18%,69.63%,0.8797和0.6131.模型分析结果表明:影响酶切位点选择性的氨基酸性质由大到小依次为:疏水性、电性和立体特征;P9,P8,P4,P1,P3’,P4’和P5’位氨基酸对酶切位点的选择有重要影响,研究亦显示酶切位点上游P1位和下游P1’～P5’的"疏水势差"有利于蛋白酶体的切割作用.     

虚拟原子探针随机采样法用于氨基酸结构描述及其构效关系研究

考虑药物与蛋白质受体的3类非键作用模式, 利用8类虚拟原子探针和Monte Carlo随机采样技术, 得到了一套新的氨基酸侧链表面静电、立体及疏水势能场(ASSPF)参数. 在此基础上对苦味二肽和血管舒缓激五肽进行了结构表征和QSAR研究, 所建模型复相关系数R2和留一法交互检验复相关系数QLOOCV2分别为0.8457, 0.851和0.7688, 0.7952, 同时分析了肽链不同位置上氨基酸侧链对活性的影响, 取得较好的结果.     

HLA-A*0201限制性CTL表位定量结构与活性研究

采用VHSE氨基酸结构描述子表征HLA-A*0201限制性表位结构, 以遗传算法和偏最小二乘相结合(GA-PLS)对102个训练集进行定量构效关系建模. 剔除3个异常样本后, 据候选模型交互检验及50个外部测试集预测结果, 筛选得到最优偏最小二乘模型(A＝2), 其R², Q²和 分别为0.755, 0.621和0.680. 构效研究显示: CTL表位活性主要与1, 2, 7, 8, 9位氨基酸残基疏水、1, 2位立体及6位残基电性等性质密切相关.     

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.     

Structural characterization of a rigidified threading bisintercalator

NMR spectroscopy was used to explore the sequence-specific interaction of DNA with a new threading bisintercalator (C1) consisting of two intercalating 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) units connected by a rigid, tricyclic spiro linker. A structural model of C1 complexed to d(CGGTACCG)(2) was calculated using distance constraints obtained from solution NMR data. The model was also supported by the results from residual dipolar coupling (RDC) measurements obtained using Pf1-phage as a cosolvent. According to the model, the central cyclohexane ring of the linker connecting the two NDI units lies flat in the minor groove of DNA. Linker length, hydrogen bonding, steric, and hydrophobic factors all appear to contribute to the observed sequence specificity of binding. These results serve to illustrate the versatility of threading polyintercalation given that, in a previous study, a ligand consisiting of two NDI units joined by a flexible peptide linker was shown to bind sequence specifically within the major groove of this same sequence of DNA.     

Quantum-chemical foundations of the topological substructural molecular design

The topological substructural molecular design (TOPS-MODE) approach is formulated as a tight-binding quantum-chemical method. The approach is based on certain postulates that permit to express any molecular property as a function of the spectral moments of certain types of molecular and environment-dependent energies. We use several empirical potentials to account for these intrinsic and external molecular energies. We prove that any molecular property expressed in terms of a quantitative structure-property and structure-activity relationships (QSPR/QSAR) model developed by using the TOPS-MODE method can be expressed as a bond additivity function. In addition, such a property can also be expressed as a substructural cluster expansion function. The conditions for such bond contributions being transferable are also analyzed here. Several new statistical-mechanical electronic functions are introduced as well as a bond-bond thermal Green's function or a propagator accounting for the electronic hopping between pairs of bonds. All these new concepts are applied to the development and application of a new QSAR model for describing the toxicity of polyhalogenated-dibenzo-1,4-dioxins. The QSAR model obtained displays a significant robustness and predictability. It permits an easy structural interpretation of the structure-activity relationship in terms of bond additivity functions, which display some resemblances with other theoretical parameters obtained from first principle quantum-chemical methods.     

Triple hydrogen bonding in a circular arrangement: ab initio, DFT and first-principles MD studies of tris-hydroxyaryl enamines

First-principles Car-Parrinello molecular dynamics, ab initio (MP2) and density functional schemes have been used to explore the tautomeric equilibrium in three tris(amino(R)methylidene)cyclohexane-1,3,5-triones (R?=?hydrogen, methyl or phenyl group). The dynamic nature of the cyclic hydrogen bonding has been studied by the first-principles MD method. The comparison of the results obtained by aforesaid methods has been accomplished on the basis of calculations of structural and spectroscopic characteristics of the compounds. The conformational analysis of the studied compounds has been carried out at the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels of theory. The influence of steric and electronic effects on the cyclic hydrogen bonding has been analysed. The extent of the proton delocalization has been modified by the substituents according to the sequence: hydrogen?<?phenyl?<?methyl. This fact is verified by the spectroscopic and structural data as well as the energy potential curve. A prevalence of the keto-enamine tautomeric form has been observed in the static ab initio and DFT models, and confirmed by the first-principles MD.     

三维全息原子场作用矢量(3D-HoVAIF)用于神经氨酸酶抑制剂的结构表征与设计及定量构效关系(QSAR)研究

对100个神经氨酸酶抑制剂抗禽流感药物结构并与其活性建立定量构效关系模型。采用本实验室提出的三维全息原子场作用矢量(3D-HoVAIF)对100个神经氨酸酶抑制剂进行结构表征,然后采用逐步回归对变量进行筛选后,运用偏最小二乘建立3D-HoVAIF描述子与神经氨酸酶抑制剂活性之间的QSAR模型。结果表明:复相关系数(R),交互校验的复相关系数(Q2)和模型的标准偏差(SD)分别为R2=0.805、Q2=0.657和SD=0.936,模型具有良好的稳定性和预测能力,并对文献中23个药物和设计的32个化合物进行了预测。表明三维全息原子场作用矢量能较好表征该类分子结构信息值得进一步推广应用。