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.     

Comparative docking and CoMFA analysis of curcumine derivatives as HIV-1 integrase inhibitors

The docking studies and comparative molecular field analysis (CoMFA) were performed on highly active molecules of curcumine derivatives against 3′ processing activity of HIV-1 integrase (IN) enzyme. The optimum CoMFA model was selected with statistically significant cross-validated r² value of 0.815 and non-cross validated r ² value of 0.99. The common pharmacophore of highly active molecules was used for screening of HIV-1 IN inhibitors. The high contribution of polar interactions in pharmacophore mapping is well supported by docking and CoMFA results. The results of docking, CoMFA, and pharmacophore mapping give structural insights as well as important binding features of curcumine derivatives as HIV-1 IN inhibitors which can provide guidance for the rational design of novel HIV-1 IN inhibitors.     

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.     

Molecular dynamics directed CoMFA studies on carbocyclic neuraminidase inhibitors

Zanamivir is the known potent anti-influenza agent targeting the key enzyme neuraminidase that cleaves sialic acid from cell receptors allowing release of newly formed virions. Molecular dynamics simulation was carried out to determine the dynamic behavior of Zanamivir upon its binding to flexible loops of neuraminidase and to analyse its interactions in the bioactive state. Neuraminidase exhibits wide range of affinity with structurally similar compounds. CoMFA study was used to determine quantitative structure-activity relationship for 36 carbocyclic Neuraminidase inhibitors (NIs). The CoMFA model was also successfully built using cross-validated r²_cv = 0.580{{r}^{2}_{\rm cv} =0.580} and r²_pred=0.638{{r}^{2}_{\rm pred}=0.638} .     

3D-QSAR,molecular dynamics simulations,and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors

Cancer is a second major disease after metabolic disorders where the number of cases of death is increasing gradually. Mammalian target of rapamycin (mTOR) is one of the most important targets for treatment of cancer, specifically for breast and lung cancer. In the present research work, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were performed on 50 compounds reported as mTOR inhibitors. Three different alignment methods were used, and among them, distill method was found to be the best method. In CoMFA, leave-one-out cross-validated coefficients \((q^{2})\), conventional coefficient \((r^{2})\), and predicted correlation coefficient \((r^{2}_{\mathrm{pred}})\) values were found to be 0.664, 0.992, and 0.652, respectively. CoMSIA study was performed in 25 different combinations of features, such as steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic. From this, a combination of steric, electrostatic, hydrophobic (SEH), and a combination of steric, electrostatic, hydrophobic, donor, and acceptor (SEHDA) were found as best combinations. In CoMSIA (SEHDA), \(q^{2}\), \(r^{2}\) and \(r^{2}_{\mathrm{pred}}\) were found to be 0.646, 0.977, and 0.682, respectively, while in the case of CoMSIA (SEH), the values were 0.739, 0.976, and 0.779, respectively. Contour maps were generated and validated by molecular dynamics simulation-assisted molecular docking study. Highest active compound 19, moderate active compound 15, and lowest active compound 42 were docked on mTOR protein to validate the results of our molecular docking study. The result of the molecular docking study of highest active compound 19 is in line with the outcomes generated by contour maps. Based on the features obtained through this study, six novel mTOR inhibitors were designed and docked. This study could be useful for designing novel molecules with increased anticancer activity.     

A combined 3D-QSAR and molecular docking strategy to understand the binding mechanism of V600EB-RAF inhibitors

B-RAF is a member of the RAF protein kinase family involved in the regulation of cell growth, differentiation, and proliferation. It forms a part of conserved apoptosis signals through the RAS?CRAF?CMAPK pathway. ^V600EB-RAF protein has much potential for scientific research as therapeutic target due to its involvement in human melanoma cancer. In this work, a molecular modeling study was carried out for the first time with 3D-QSAR studies by following the docking protocol on three different data sets of ^V600EB-RAF inhibitors. Based on the co-crystallized compound (PDB ID: 1UWJ), a receptor-guided alignment method was utilized to derive reliable CoMFA and CoMSIA models. The selected CoMFA model gives the best statistical values (q ² =?0.753, r ² =?0.962). With the same alignment protocol, a statistically reliable CoMSIA model out of fourteen different combinations was also derived (q ² = 0.807, r ² = 0.961). The actual predictive powers of both models were rigorously validated with an external test set, which gave satisfactory predictive r ² values for CoMFA and CoMSIA models, 0.89 and 0.88, respectively. In addition, y-randomization test was also performed to validate our 3D-QSAR models. Contour maps from CoMFA and CoMSIA models supported statistical results, revealed important structural features responsible for biological activity within the active site and explained the correlation between biological activity and receptor?Cligand interactions. Based on the developed models few new structures were designed. The newly predicted structure (IIIa) showed higher inhibitory potency (pIC₅₀ 6.826) than that of the most active compound of the series.     

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.     

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.     

CORAL: QSPR models for solubility of [C60] and [C70] fullerene derivatives

Quantitative structure–property relationships (QSPRs) between the molecular structure of [C₆₀] and [C₇₀] fullerene derivatives and their solubility in chlorobenzene (mg/mL) have been established by means of CORAL (CORrelations And Logic) freeware. The CORAL models are based on representation of the molecular structure by simplified molecular input line entry system (SMILES). Three random splits into the training and the external validation sets have been examined. The ranges of statistical characteristics of these models are as follows: n = 18, r ² = 0.748–0.815, s = 15.1 –17.5 (mg/mL), F = 47–71 (training set); n = 9, r ² = 0.806–0.936, s = 12.5–17.5 (mg/mL), F = 29–103 (validation set).     

Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors

The search for new antimalarial agents is necessary as current drugs in the market become vulnerable due to the emergence of resistance strains of Plasmodium falciparum (P. falciparum). The biosynthetic pathway for fatty acids has been recognized and validated as an important drug target in P.falciparum. One of the important enzymes in this pathway that has a determinant role in completing the cycles of chain elongation is Enoyl-ACP reductase (ENR) also popularly known as FabI. In this paper we report the design, synthesis, and microbial evaluation of inhibitors of Plasmodium enoyl reductase (PfENR). The search for inhibitors involved a virtual screening of the iResearch database with docking simulations. One of the hits was selected and modified to optimize its binding to PfENR; this resulted in the development of analogues of N-benzylidene-4-phenyl-1,3-thiazol-2-amine. The activity of these analogues was predicted from comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models constructed from a dataset of 43 known inhibitors of PfENR. The most promising molecules were synthesized and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity by whole-cell assay method. Two molecules, viz. VRC-007 and VRC-009, were found to be active at 4.67 and 7.01 μM concentrations, respectively.     

Parallel synthesis of novel antitumor agents: 1,2,3-triazoles bearing biologically active sulfonamide moiety and their 3D-QSAR

A 60-member 1,2,3-triazoles bearing biologically active sulfonamide moiety library was synthesized via azide–alkyne cycloaddition and examined for cytotoxic activity against human leukemia cell line HL-60. 25 of them were evaluated further in four additional cancer cell lines (HepG2, A549, PC3, SGC7901). Most of the 25 compounds showed moderate cytotoxic activities against the tested cell lines. Furthermore, the structure–activity relationships were discussed and a reliable 3D-QSAR model with good prediction (r_cv² = 0.64, r² = 0.958){\left(r_{\rm cv}^{2 } = 0.64, r^{2} = 0.958\right)} was generated on the basis of our synthesized 1,2,3-triazoles for their cytotoxic activities against the HL-60 cell line. The contour map of the CoMFA should aid in the design of new antitumor agents.     

Oxide ion conductivity and relaxation in CaREZrNbO7 (RE = La, Nd, Sm, Gd, and Y) system

CaREZrNbO₇ (RE = La, Nd, Sm, Gd and Y) system changed from fluorite (F)-type to pyrochlore (P)-type structure when the ionic radius ratios, r(Ca²⁺–RE³⁺)_av/r(Zr⁴⁺–Nb⁵⁺)_av were larger than 1.34. Thus, the La, Nd, and Sm compounds have a cubic P-type structure and the Gd and Y ones have a defect F-type structure. The electrical conductivity was measured using complex-plane impedance analysis over a wide temperature (300–750 °C) and frequency (1 Hz–1 MHz) ranges. The conductivity relaxation phenomenon was observed in these compounds and the relaxation frequencies were found to show Arrhenius-type behavior and activation energies were in good agreement with those obtained from high temperature conductivity plots. These results support the idea that the relaxation process and the conductivity have the same origin. The ionic conductivity of CaREZrNbO₇ (RE = La, Nd, Sm, Gd and Y) system showed the maximum at the phase boundary between the F-type and P-type phases. On the other hand, the activation energy for the conduction decreased in the F-type phase and increased in the P-type phase with increasing ionic radius ratio. Among the prepared compounds, CaGdZrNbO₇ showed the highest ionic conductivity of 9.47 × 10^− 3 S/cm at 750 °C which was about twice as high as that observed in Gd₂Zr₂O₇ (4.2 × 10^− 3 S/cm at 800 °C). The grain morphology observation by scanning electron microscope (SEM) showed well-sintered grains. AC impedance measurements in various atmospheres further indicated that they are predominantly oxide ion conductors at elevated temperatures (> 700 °C).     

A Random Matrix Decimation Procedure Relating <Emphasis Type="Italic">β</Emphasis> = 2/(<Emphasis Type="Italic">r</Emphasis> + 1) to <Emphasis Type="Italic">β</Emphasis> = 2(<Emphasis Type="Italic">r</Emphasis> + 1)

Classical random matrix ensembles with orthogonal symmetry have the property that the joint distribution of every second eigenvalue is equal to that of a classical random matrix ensemble with symplectic symmetry. These results are shown to be the case r = 1 of a family of inter-relations between eigenvalue probability density functions for generalizations of the classical random matrix ensembles referred to as β-ensembles. The inter-relations give that the joint distribution of every (r + 1)^st eigenvalue in certain β-ensembles with β  =  2/(r + 1) is equal to that of another β-ensemble with β  =  2(r + 1). The proof requires generalizing a conditional probability density function due to Dixon and Anderson.     

The Probability of Entanglement

We show that states on tensor products of matrix algebras whose ranks are relatively small are almost surely entangled, but that states of maximum rank are not. More precisely, let and be full matrix algebras with m ≥  n, fix an arbitrary state ω of N, and let E(ω) be the set of all states of that extend ω. The space E(ω) contains states of rank r for every r = 1, 2, . . . , m · rank ω, and it has a filtration into compact subspaces

A Construction of Blow up Solutions for Co-rotational Wave Maps

The existence of co-rotational finite time blow up solutions to the wave map problem from ${\mathbb{R}^{2+1} \to N}The existence of co-rotational finite time blow up solutions to the wave map problem from \mathbbR²⁺¹ ? N{\mathbb{R}^{2+1} \to N} , where N is a surface of revolution with metric d ρ ² + g(ρ)² dθ², g an entire function, is proven. These are of the form u(t,r)=Q(l(t)t)+R(t,r){u(t,r)=Q(\lambda(t)t)+\mathcal{R}(t,r)} , where Q is a time independent solution of the co-rotational wave map equation −u _tt  + u _rr  + r ⁻¹ u _r  = r ⁻² g(u)g′(u), λ(t) = t ^−1-ν, ν > 1/2 is arbitrary, and R{\mathcal{R}} is a term whose local energy goes to zero as t → 0.     

High diastereoselectivity induced by intermolecular hydrogen bonding in [3 + 2] cycloaddition reaction: experimental and computational mechanistic approaches

A diastereoselective [3 + 2] cycloaddition of N‐aryl substituted maleimides with N,α‐diphenyl nitrone possessing 11‐hydroxyundecyloxy as a flexible substituent was performed. Experimental and comprehensive mechanistic density functional theory studies reveals that intermolecular H‐bonding and steric repulsive interaction predominate exo‐Z and exo‐E cycloaddition transition states, respectively. The reaction proceeded smoothly depending on the reactants and gave a good yield of (syn) cis‐isoxazolidine or (anti) trans‐isoxazolidine as a single diastereomer.     

3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-activated protein kinase inhibitors

The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and psoriasis. Herein, we have performed 3D-QSAR and molecular docking analysis on a novel series of biphenyl amides to design potent p38 MAP kinase inhibitors. This study correlates the p38 MAP kinase inhibitory activities of 80 biphenyl amide derivatives to several stereochemical parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The resulting model from CoMFA and CoMSIA exhibited excellent [Formula: see text] values of 0.979 and 0.942, and [Formula: see text] values of 0.766 and 0.748, respectively. CoMFA predicted [Formula: see text] of 0.987 and CoMSIA predicted [Formula: see text] of 0.761 showed that the predicted values were in good agreement with experimental values. Glide (5.5) program gave the path for binding mode exploration between the inhibitors and p38α MAP kinase. We have accordingly designed novel p38α MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models.     

Flow versus permeability weighting in estimating the forward volumetric transfer constant (Ktrans) obtained by DCE-MRI with contrast agents of differing molecular sizes

PurposeTo quantify the differential plasma flow- (F_p-) and permeability surface area product per unit mass of tissue- (PS-) weighting in forward volumetric transfer constant (K^trans) estimates by using a low molecular (Gd-DTPA) versus high molecular (Gadomer) weight contrast agent in dynamic contrast enhanced (DCE) MRI.Materials and methodsDCE MRI was performed using a 7T animal scanner in 14 C57BL/6J mice syngeneic for TRAMP tumors, by administering Gd-DTPA (0.9 kD) in eight mice and Gadomer (35 kD) in the remainder. The acquisition time was 10 min with a sampling rate of one image every 2 s. Pharmacokinetic modeling was performed to obtain K^trans by using Extended Tofts model (ETM). In addition, the adiabatic approximation to the tissue homogeneity (AATH) model was employed to obtain the relative contributions of F_p and PS.ResultsThe K^trans values derived from DCE-MRI with Gd-DTPA showed significant correlations with both PS (r² = 0.64, p = 0.009) and F_p (r² = 0.57, p = 0.016), whereas those with Gadomer were found only significantly correlated with PS (r² = 0.96, p = 0.0003) but not with F_p (r² = 0.34, p = 0.111). A voxel-based analysis showed that K^trans approximated PS (< 30% difference) in 78.3% of perfused tumor volume for Gadomer, but only 37.3% for Gd-DTPA.ConclusionsThe differential contributions of F_p and PS in estimating K^trans values vary with the molecular weight of the contrast agent used. The macromolecular contrast agent resulted in K^trans values that were much less dependent on flow. These findings support the use of macromolecular contrast agents for estimating tumor vessel permeability with DCE-MRI.