吡啶并嘧啶类Wee1激酶衍生物的三维定量构效关系与分子对接

采用比较分子场分析方法(CoMFA)和比较分子相似性指数分析方法(CoMSIA)对一系列吡啶并嘧啶类衍生物进行了三维定量构效关系(3D-QSAR)研究,建立了CoMFA和CoMSIA两种模型. 所构建的最佳模型的交叉验证相关系数分别为0.707和0.645,非交叉验证系数分别是0.964和0.972,模型的一些外部验证表明两个模型合理、可靠,并具有良好的预报能力. 同时,用分子对接的方法分析了该类化合物与Wee1激酶结构的作用模式,结果进一步表明,在R1和R5取代基上引入正电性基团,R2为体积小的电负性基团,同时选择体积中等和强的推电子的R3但亲水性的X取代基,能有效改善这类化合物的抑制活性.     

Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H ₃₇Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3–93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r ²) of 0.98 and 0.95 with cross-validated r ²(q ²) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive ${r^{2} (r^{2}_{\rm pred})}$ is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.     

De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q ², 0.671; r ², 0.969; CoMSIA with q ², 0.608; r ², 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein?Cligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.     

Comparative molecular field analysis and comparative molecular similarity indices analysis of hydroxyethylamine derivatives as selective human BACE-1 inhibitor

Three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), on a series of 43 hydroxyethylamine derivatives, acting as potent inhibitors of β-site amyloid precursor protein (APP) cleavage enzyme (BACE-1). The crystal structure of the BACE-1 enzyme (PDB ID: 2HM1) with one of the most active compound 28 was available, and we assumed it to be the bioactive conformation of the studied series, for 3D-QSAR analysis. Statistically significant 3D-QSAR model was established on a training set of 34 compounds, which were validated by a test set of 9 compounds. For the best CoMFA model, the statistics are, r ² =  0.998, r²_cv = 0.810{r^{2}_{\rm cv} = 0.810} , n =  34 for the training set and r²_pred = 0.934{r^{2}_{\rm pred} = 0.934} , n = 9 for the test set. For the best CoMSIA model (combined steric, electrostatic, hydrophobic, and hydrogen bond donor fields), the statistics are r ² =  0.978, r²_cv = 0.754{r^{2}_{\rm cv} = 0.754} , n =  34 for the training set and r²_pred = 0.750{r^{2}_{\rm pred} = 0.750} , n =  9 for the test set. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. The data generated from the present study will further help to design novel, potent, and selective BACE-1 inhibitors.     

CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements

The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q ² of 0.651 with a non-cross-validated r ² of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q ² = 0.661; non-cross-validated r ² = 0.803; external test set’s predictive r ² = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.     

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

对一系列具有抗人乳腺癌细胞系MCF-7生物活性的微管蛋白抑制剂─芳基硫代吲哚衍生物(arylthioindole),进行了三维定量构效关系(3D-QSAR)和对接(docking)研究. 在训练集中,建立了具有良好统计质量和预报能力的比较分子力场分析(CoMFA) 模型,其非交叉验证相关系数平方R₂为0.898,交叉验证相关系数平方q₂为0.654. 同时在测试集的验证中得到预测相关系数平方R₂(pred)为0.816, 进一步表明了该模型具有较高的预测能力. 此外,通过对接研究,获得了这些化合物与微管蛋白作用的键合方式和构象,发现该系列化合物的CoMFA力场分布与对接结合位点上的三维拓朴结构相一致. 根据CoMFA和对接分析的结果,细致地讨论和总结了有利于提高或改进该类化合物活性的主要因素,即在取代基R3、R4和R5上引进高电负性的基团,在取代基R6上引进带有高电负性且大体积的基团,以及在取代基R7上引进小体积的基团等都是有利的. 基于这些研究结果,在理论上还设计了5个新的具有较高活性的化合物.     

High-pressure phases of CuI studied by129I-Mössbauer spectroscopy

The results of an¹²⁹I-Mössbauer study of the high-pressure phases of CuI at 4.2 K and for external pressures up to 71 kbar are reported. The isomer shiftS and the electric quadrupole interactionE _q are found to undergo larges discontinuities at the crystallographic phase-transition pressures of ?18 kbar from zinc-blence to rhombohedral structure and at ?46 kbar from rhombohedral to tetragonal. The pressure coefficients of these hyperfine parameters are significantly different for the three phases (zinc-blende; rhombohedral; tetragonal) dS/dP=?3.3; =+1.5; =2.5×10^?3 mm/s/kbar; dE _q/dP=0.0; =?0.92;=+0.31 Mc/s/kbar. These results cannot be explained in terms of a simple molecular-orbital picture; instead, they reflect pressure-induced variations of the halogen-p/metal-d hybridization in the valence bands of the various phases of CuI.     

Mössbauer spectroscopy and DFT calculations on all protonation states of the 2Fe-2S cluster of the Rieske protein

The Thermus thermophilus Rieske protein (TtRP) contains a 2Fe-2S cluster with one iron (Fe-Cys) coordinated by four sulfur atoms (2xS^2? and 2xCys) and one iron (Fe-His) by two sulfur and two nitrogen atoms (2xS^2?, His134 and His154). Here, the protein is investigated at three pH values (6.0, 8.5 and 10.5) in order to elucidate the protonation states of the His-ligands. Examination of the effect of protonation on the electronic structure of the cluster via Mössbauer spectroscopy gives a deeper understanding of the coupling of electron transfer to the protonation state of the His-ligands. Two components (1 referring to Fe-Cys and 2 to Fe-His) with parameters typical for a diamagnetic [2Fe-2S]²⁺ cluster are detected. The Mössbauer parameters and the protonation state clearly correlate: while δ remains almost pH-independent with δ ₁ (pH6.0) =?0.23 (±?0.01) mms^??1 and δ ₁ (pH10.5) =?0.24 (±?0.01) mms^??1 for Fe-Cys, it decreases for Fe-His from δ ₂ (pH6.0) =?0.34 (±?0.01) mms^??1 to δ ₂ (pH10.5) =?0.28 (±?0.01) mms^??1. ΔE _Q changes from ΔE _Q1 (pH6.0) =?0.57 (±?0.01) mms^??1 to ΔE _Q1 (pH10.5) =?0.45 (±?0.01) mms^??1 and from ΔE _Q2 (pH6.0) =?1.05 (±?0.01) mms^??1 to ΔE _Q2 (pH10.5) =?0.71 (±?0.01) mms^??1. Density functional theory (DFT)-calculations based on the crystal structure (pdb 1NYK) (Hunsicker-Wang et al. Biochemistry 42, 7303, 2003) have been performed for the Rieske-cluster with different His-ligand protonation states, reproducing the experimentally observed trend.     

Macdonald Polynomials in Superspace: Conjectural Definition and Positivity Conjectures

We introduce a conjectural construction for an extension to superspace of the Macdonald polynomials. The construction, which depends on certain orthogonality and triangularity relations, is tested for high degrees. We conjecture a simple form for the norm of the Macdonald polynomials in superspace and a rather non-trivial expression for their evaluation. We study the limiting cases q =?0 and q =???, which lead to two families of Hall?CLittlewood polynomials in superspace. We also find that the Macdonald polynomials in superspace evaluated at q =?t =?0 or q =?t = ?? seem to generalize naturally the Schur functions. In particular, their expansion coefficients in the corresponding Hall?CLittlewood bases appear to be polynomials in t with nonnegative integer coefficients. More strikingly, we formulate a generalization of the Macdonald positivity conjecture to superspace: the expansion coefficients of the Macdonald superpolynomials expanded into a modified version of the Schur superpolynomial basis (the q = t =?0 family) are polynomials in q and t with nonnegative integer coefficients.     

Determination of the orientation of the electric field gradient at the Cu(1) site from the Mössbauer spectra of textured pellets made of YBa2Cu3O7−δ superconductor

A textured pellet of YBa₂Cu₃O_7?δ was prepared and doped with⁵⁷Co. After subsequent heat treatments the cobalt was found at the two copper sites. The degree of alignment of individual crystallites (about 40%) was determined from the Mössbauer spectrum by using a method developed by the authors [1]. The same method showed that the most characteristic doublet component of such spectra (δ=0.08 mm/s; |ΔE _Q|=1.96 mm/s) is associated with a site, most probably a Cu(1) site, where the EFG is parallel to thec direction of the unit cell. The sign ofV _zz turned out to be negative, giving a negative quadrupole splitting (ΔE _Q=?1.96 mm/s) for that component.     

Noneikonal approach to the scattering of hadrons from nuclei III. pd scattering at intermediate energy

A noneikonal theory, formulated originally for hadron scattering by spherically symmetric nuclei, is extended to the case of nonspherical densities. The results are applied to 600-MeV and 1-GeV proton elastic scattering by polarized and aligned deuterons. Around the diffraction minimum 0.2 ? q² ? 0.6 (GV/c)², and for large q² ? 1 (GeV/c)², our predictions for the differential cross section differ considerably from those obtained in Glauber theory. Experimental checks of our predictions are discussed.     

Observation of new nuclides37Si,40P,41S,42S produced in deeply inelastic reactions induced by40Ar on238U

A non-relativistic quantum-mechanical system is studied which consists ofN identical bosons interacting by pair potentials of the form 〈r¦V¦r ¹〉=?π/2ν ₀ a ^?3 f(r/a)f ^*(r ¹/a). General upper and lower bounds to the ground-state energyE _N are provided for alla, V ₀ andN, and detailed results are given in the case of the Yamaguchi potential for whichf(x)=e ^?x/x. It is shown that the ratioE _N /E ₂ diverges both under the limit (i) a↓0,E ₂ =arbitrary constant <0, and (ii) (V ₀ a ²)↓(V ₀ a ²)_c, where (V ₀ a ²) _c corresponds toE ₂=0. The results complement recent studies of the Efimov effect via scattering theory.     

Searches for the superheavy hydrogen isotope 7H in the absorption of stopped π − mesons

Experimental searches for the superheavy hydrogen isotope ⁷H were performed in reactions involving the absorption of stopped π ^? mesons on ⁹Be and ¹¹B nuclei. In the reaction ⁹Be(π ^?, pp)X, the missing-mass spectrum shows evidence for the formation of ⁷H states, that of E _r = 16 ± 1 MeV and Γ ? 2 MeV and that of E _r = 21 ± 1 MeV and Γ ? 5 MeV (E _r is the resonance energy with respect to breakup into a trition and four neutrons, and Γ is the observed level width).     

Electromagnetic form factors of nucleons in a relativistic square-root potential model of independent quarks

The nucleon electromagnetic form factorsG _E ^P (q²),G _M ^P (q²) and the axial-vector form factor G_A(q²) are studied in a relativistic model of independent quarks confined by an equally mixed scalar-vector square root potentialV _q(r)=1/2(1+γ ⁰)(ar ^1/2+ν ₀) taking into account the appropriate centre-of-mass corrections. The respective root-mean-square radii associated withG _E ^P (q²) and G _A (q²) come out as [〈r ²〉 _E ^P ]^1/2=0.86 fm and 〈r _A ² 〉^1/2=0.88 fm. Restoration of chiral symmetry in this model is discussed to derive the pion-nucleon form factorG _πNN(q²) and consequently the pion-nucleon coupling constant is obtained asg _πNN(q²)=12.81 as compared tog _πNN(q²)_exp⋍13.     

On the determination of the proton RMS-radius from electron scattering data

It is shown that the proton rms radius should be determined from fitting a polynomial of second order to the low-q ² form factors. The commonly used polynomial of first order yields radius values which are too small. The proton rms radius has been redetermined from an analysis of the electron scattering data measured at three laboratories. The best fit value is 〈r _E ² 〉^1/2=0.87±0.02 fm.