Field Analysis Techniques Research Articles

3D-QSAR and docking study on 3-benzimidazol-2-ylhydroquinolin-2-one derivatives as VEGFR-2 tyrosine kinase inhibitors

The present study is an attempt to formulate the three-dimensional quantitative structure–activity relationship (3D-QSARs) modeling of 3-benzimidazol-2-ylhydroquinolin-2-one derivatives inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. The 3D-QSARs were established for 36 3-benzimidazol-2-ylhydroquinolin-2-one derivatives as VEGFR-2 tyrosine kinase inhibitors using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) techniques. The negative logarithm of IC50 (pIC50) was used as the biological activity in the 3D-QSAR study. With the CoMFA model, the cross-validated value (q2) was 0.516, the non-cross-validated value (R2) was 0.927, and the external cross-validated value (Qext2) was 0.855; with the CoMSIA model, the corresponding q2, R2, and Qext2 values were 0.538, 0.980, and 0.809, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified test set of nine compounds. Then, molecular docking was carried out to better understand of the interactions between VEGFR-2 tyrosine kinase target and inhibitors. Finally, based on results of the structure–activity relationship and of the molecular docking, seven VEGFR-2 tyrosine kinase inhibitors that showed excellent potencies have been constructed.

Investigations and design of pyridine-2-carboxylic acid thiazol-2-ylamide analogs as methionine aminopeptidase inhibitors using 3D-QSAR and molecular docking

Methionine amino peptidases (MetAPs) are metalloproteases that remove co-translational N-terminal methionine from nascent polypeptide chains. Due to their essential role in protein synthesis, MetAPs are considered as potential targets for antibacterial drugs. In the present work, three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of pyridine-2-carboxylic acid thiazol-2-ylamide-based MetAP inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models were developed using 30 training set molecules. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients (q 2) of 0.799 and 0.704 and conventional correlation coefficients (r 2) of 0.989 and 0.954, respectively. These inhibitors were docked into MetAP active site. The CoMFA and CoMSIA field contour maps correlate well with the structural characteristics of the binding pocket of MetAP active site. Using the knowledge of structure–activity relationship and receptor–ligand interactions from 3D-QSAR model and the docked complexes, four new pyridine-2-carboxylic acid thiazol-2-ylamide analogs were designed. These analogs exhibit significantly better predicted activity than the reported molecules. The present work has implications for the development of novel antibiotics as potent MetAP inhibitors.

A systematic quantitative approach to rational drug design and discovery of novel human carbonic anhydrase IX inhibitors

Drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase IX inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques with the help of SYBYL 7.1 software. The large set of 36 different aromatic/heterocyclic sulfamates carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA IX, was chosen for this study. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q2 values 0.802 and 0.829 and r2 values 1.000 and 0.994 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. The predicted r2 values are 0.999 and 0.502 for CoMFA and CoMSIA, respectively. SEA (steric, electrostatic, hydrogen bond acceptor) of CoMSIA has the significant contribution for the model development. The docking of inhibitors into hCA IX active site using Glide XP (Schrödinger) software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps are well in agreement with the structural characteristics of the binding pocket of hCA IX active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin.

3D-QSAR Studies of Tetraoxanes Derivatives as Antimalarial Agents Using CoMFA and CoMSIA Approaches

Tetraoxanes (1,2,4,5-tetraoxanes) have been reported to exhibit potent antimalarial activity. In the present study, the three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of tetraoxanes derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best predictive CoMFA model with atom fit alignment resulted in cross-validated coefficient () value of 0.719, non-cross-validated coefficient () value of 0.855 with standard error of estimate (SEE) 0.335. Similarly, the best predictive CoMSIA model was derived with of 0.739, of 0.847 and SEE of 0.344. The generated models were externally validated using test sets. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel tetraoxanes having improved antimalarial activity.

Experimental and Analytical Study on DC Breakdown Characteristics of Butt Gap Condition in $\hbox{LN}_{2}/\hbox{PPLP}$ Composite System

Due to ac loss in superconducting materials, high cryogenic costs are inevitable when superconducting devices are operated in ac power networks. Thus, dc electric power networks would be regarded as a better choice for the operation of superconducting devices. In order to develop superconducting devices for a dc network, the dc insulation characteristics, which are much different from the ac insulation characteristics, should be clarified. In this paper, in order to investigate the dc insulation characteristics of polypropylene laminated paper (PPLP), which is generally used for dc superconducting cable, a dc breakdown test and a dc electric field analysis were performed. For the dc breakdown test, specimens with three layers of PPLP with one butt gap were fabricated. In order to reveal the breakdown characteristic of PPLP, a dc electric fields calculation in the media at the moment of breakdown was performed considering capacitive and resistive field distributions. Consequently, the capacitive electric field and resistive electric field distributions were determined using dc field analysis techniques and it was found that the butt gap edge is affected enough by the high field strength to cause the breakdown. Furthermore, it was deduced that the butt gap edge acted as a triple-junction point which causes the breakdown.

Discovery of new potential hits of Plasmodium falciparum enoyl-ACP reductase through ligand- and structure-based drug design approaches

We here report the discovery of novel Plasmodium falciparum enoyl-ACP reductase (PfENR) inhibitors as new antimalarial hits through ligand- and structure-based drug design approaches. We performed 2D and 3D QSAR studies on a set of rhodanine analogues using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Statistical and satisfactory results were obtained for the best HQSAR (r2 of 0.968 and qLOO2 of 0.751), CoMFA (r2 of 0.955 and qLOO2 of 0.806) and CoMSIA (r2 of 0.965 and qLOO2 of 0.659) models. The information gathered from the QSAR models guided us to design new PfENR inhibitors. Three new hits were predicted with potency in the submicromolar range and presented drug-like properties.

Structure determinants of indolin-2-on-3-spirothiazolidinones as MptpB inhibitors: An in silico study

Tuberculosis caused by Mycobacterium tuberculosis (Mtb), is a major factor of death around the world. Mtb protein tyrosine phosphatase B (MptpB), a virulent phosphatase encoded by Mtb, is a potential target for the treatment of tuberculosis. To explore the structure features of 134 indolin-2-on-3-spirothiazolidinones as MptpB inhibitors, in this work, a set of ligand- and receptor-based 3D-QSAR studies were, for the first time, carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. Splitting of the training and test sets was constructed by Kohonen's self-organizing map algorithm. Additionally, to profile the possible binding modes of these inhibitors, molecule docking and molecular dynamics (MD) simulations were performed as well. The optimal QSAR models built on both ligand- and receptor-based alignments exhibit proper reliabilities and predictive abilities as illustrated by their statistical results that for ligand-based alignment CoMFA and CoMSIA models obtain Q2 = 0.662, Rncv2 = 0.799, Rpre2 = 0.757, and Q2 = 0.736, Rncv2 = 0.847, Rpre2 = 0.866; whereas for docking-based one achieve Q2 = 0.536, Rncv2 = 0.894, Rpre2 = 0.823, and Q2 = 0.498, Rncv2 = 0.812, Rpre2 = 0.833, respectively. Furthermore, the contours generated from these models are well consistent with the docking and MD results we performed. Our findings are: (1) Indolin-2-on-3-spirothiazolidinones may bind to the MptpB with a “cockhorse” conformation, which is stabilized by eight H-bonds formed with the surrounding residues (Arg166, Cys160, Ala162, Lys164, His94 and Glu129), one cation–π interaction with the side chain of Arg166 and two hydrophobic interactions in the binding site. (2) Introduction of bulky and electropositive substituents at R3, hydrophobic substituents around rings A and E can improve the inhibition potency. (3) Nitro group at R2 position of 2-oxindole core plays a crucial role for the biological activities, and may also be essential to the water-mediated H-bond networks. (4) For 8, 10-positions of the thiazolidinone ring and 13-position of isoxazole, the groups acting as H-bond acceptor are favorable for increasing the activity. All these results are expected to be useful in the discovery of novel and more potent MptpB inhibitors.

Human Androgen Receptor Inhibitors: Computational 3D QSAR Studies to Design Lead Compounds for Treatment of Prostate Cancer

Objectives: The inhibition of Androgen receptors have been vigorously pursued as a promising target for the treatment of prostate cancer. A set of 40 training set compounds and 20 test set compounds reported as Androgen receptors inhibitors were analyzed by employing the molecular field analysis (MFA) and Receptor surface analysis (RSA) techniques to investigate the structural requirements for various analogues to inhibit Androgen receptors and to derive a highly predictive model used for the designing of novel Androgen receptors inhibitors. Material and Methods: Pharmacophore generation and 3D-QSAR studies have been performed for developing novel Androgen Receptors inhibitors using Cerius2 and Catalyst programs. QSAR equations have been generated for 40 Androgen Receptors inhibitors employing Molecular Field Analysis (MFA) as well as Receptor surface Analysis (RSA) using Genetic function approximation (GFA) as regression method. Results: The best equations with training set produced r2 value of 0.856 and r2cv value of 0.739 in 2D-mode, r2 value of 0.839 and r2cv value of 0.793 in MFA-model and r2 value of 0.910 and r2cv of 0.856 in the RSA-model. For the 20 test set molecules predicted activities, had a correlation of 0.840 and 0.856 for MFA and RSA with observed activities. Conclusion: The 3D–QSAR models exhibited good correlation and predictive ability. The model showed that steric (CH3) and electrostatic (H +) interactions play an important role in the inhibition of Androgen receptor by the analogues. The model generated could be exploited for further structural modification in order to improve Androgen receptor inhibition activity.

Molecular Docking, QSAR and Molecular Dynamics Simulation on Spiro-oxindoles as MDM2 Inhibitors

Inhibition of the MDM2-p53 interaction is considered to be a new therapeutic strategy to activate wild-type p53 in tumors. Recently, a series of potent and specific small-molecule spiro-oxindole inhibitors of the MDM2 were reported. In the current study, the interaction modes between 21 spiro-oxindole MDM2 inhibitors and the protein were studied by using the combination of molecular docking, molecular dynamics simulation and three-dimensional quantitative structure-activity relationships (3D-QSAR). The QSAR predictive models were established by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) techniques. The predictive power of the 3D-QSAR models were determined from external test sets that were excluded during model development. The inhibitors in test sets were given exactly the same pretreatment as the inhibitors in the corresponding training sets. The correlation between the experimental and predicted activity for all models was calculated as a predictive r 2 value. With the CoMFA model, the cross-validated value (q 2 ) was 0.573, the non-cross-validated value (r 2 ) was 0.948. And with the CoMSIA model, the corresponding q 2 and r 2 were 0.651 and 0.98, respectively. The interaction mode obtained by molecular docking was in agreement with the results of molecular dynamics simulations, the interaction mode revealed that the hydrophobic interaction and H-bond played an im- portant role in the binding of spiro-oxindole derivatives and MDM2. Compounds designed by our group were synthesized and tested their in vitro cytotoxic activities against the MDM2 positive prostatic carcinoma LNCaP cell line. Two com- pounds, namely 5 and 6, with favorable scores from the CoMFA and CoMSIA models, showed potent cytotoxic activities with IC50 values lower than 1.0 μgmL -1 . The result was corresponding with that in experiment. And it was very significance to discover novel spiro-oxindole inhibitors which are mainly aimed at the MDM2-p53 interaction. It was expected that the information provided here was helpful for the study toward more accurate structure based on 3D-QSAR modeling and anti-tumor drug design and discovery. Keywords spiro-oxindole derivatives; molecular docking; molecular dynamics; comparative molecular field analysis; comparative molecular similarity indices analysis

Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: An in silico analysis

Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q2 of 0.584, Rncv2 of 0.884 and Rpre2 of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the π–π stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27-position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and π–π stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity.

Enhancement of electrical insulation performance in power equipment based on dielectric material properties

Research and development results of enhancement techniques of electrical insulation performance for higher electric field application in power transmission/substation equipment, such as transformers, switchgears and cables, are described, especially based on the view point of dielectric materials. Firstly, the electric field analysis, field optimization and field measurement techniques are introduced to discuss higher electric field stress applications in power equipment. Secondly, material types, including gases, liquids, solids, vacuum and their composite systems are discussed to make power equipment with higher insulation performance, lower losses, lower environmental impact and higher reliability. In the process of development, a highly sophisticated new approach to clarify the physical mechanisms of partial discharges was developed and applied. By the introduction and applications of the above mentioned new electrical insulation techniques based on dielectric materials, concepts of future power equipment with higher electric field stress are proposed. This paper is based on the Whitehead Memorial Lecture given at the IEEE Conference on Electrical Insulation and Dielectric Phenomena (CEIDP) 2011 in Cancun, Mexico.

Pharmacophore and Molecular Docking Guided 3D-QSAR Study of Bacterial Enoyl-ACP Reductase (FabI) Inhibitors

Enoyl acyl carrier protein (ACP) reductase (FabI) is a potential target for the development of antibacterial agents. Three-dimensional quantitative structure-activity relationships (3D-QSAR) for substituted formamides series of FabI inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore and molecular docking methods were used for construction of the molecular alignments. A training set of 36 compounds was performed to create the 3D-QSAR models and their external predictivity was proven using a test set of 11 compounds. Graphical interpretation of the results revealed important structural features of the formamides related to the active site of FabI. The results may be exploited for further optimization of the design of new potent FabI inhibitors.

3D-QSAR Study of Some Heterocyclic Sulfonamide Analogs as hCAII Inhibitors

Three-dimensional quantitative structure-activity relationship (3-D QSAR) was performed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques in order to understand the carbonic anhydrase inhibition activity. A large number of 25 structurally and functionally diverse series of aromatic heterocyclic sulfonamides carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA II were chosen for the study. Based on the alignment generated by docking conformations, a highly predictive comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed with q2 value of 0.532 and 0.486 & r2 value of 0.978 and 0.952, respectively. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to respective contours. This integrated molecular docking based alignment followed by 3D-QSAR studies should provide further insights to support structure based design of human carbonic anhydrase II inhibitors with improved activity profile.

Variable-grid technique for sound field analysis using the constrained interpolation profile method

Variable-grid technique for sound field analysis using the constrained interpolation profile method

A multi-scale enriched model for the analysis of masonry panels

A multi-scale model for the structural analysis of the in-plane response of masonry panels, characterized by periodic arrangement of bricks and mortar, is presented. The model is based on the use of two scales: at the macroscopic level the Cosserat micropolar continuum is adopted, while at the microscopic scale the classical Cauchy medium is employed. A nonlinear constitutive law is introduced at the microscopic level, which includes damage, friction, crushing and unilateral contact effects for the mortar joints. The nonlinear homogenization is performed employing the Transformation Field Analysis (TFA) technique, properly extended to the macroscopic Cosserat continuum. A numerical procedure is developed and implemented in a Finite Element (FE) code in order to analyze some interesting structural problems. In particular, four numerical applications are presented: the first one analyzes the response of the masonry Representative Volume Element (RVE) subjected to a cyclic loading history; in the other three applications, a comparison between the numerically evaluated response and the micromechanical or experimental one is performed for some masonry panels.

Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

3D-QSAR and molecular docking studies of 2-pyrimidinecarbonitrile derivatives as inhibitors against falcipain-3

The three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of falcipain-3 inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 42 molecules served to establish the QSAR models. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients r(cv)(2) (q(2)) of 0.549 and 0.608, and conventional correlation coefficients (r(2)) of 0.976 and 0.932, respectively. An independent test set of 12 molecules validated the external predictive power of both models with predicted correlation coefficients (r(pred)(2)) for CoMFA and CoMSIA as 0.697 and 0.509, respectively. The docking of inhibitors into falcipain-3 active site using GOLD software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of falcipain-3 active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved falcipain-3 inhibitors.

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

Design of a New Micro-Gripper Based on Piezoelectric Bimorphs

Considering assembly and disassembly of micro-gripper, connection and isolation of lead, a new micro-gripper based on piezoelectric bimorphs is designed by using finite element analysis. First, a detailed structure of the micro-gripper is designed based on piezoelectric bimorph cantilevered beams. Second, static and dynamic characteristics of the micro-gripper are analyzed by piezoelectric coupling field analysis technique of ANSYS. For the static performance, there is a linear relationship between displacement and driving voltage of the micro-gripper. The maximum displacement of the micro-gripper finger is about 81.9 μm under the maximum driving voltage 200 V. For dynamic performance, the natural frequency and the response time of the gripper is about 45 Hz and 1.1 ms, respectively. The micro-gripper could meet the designed needs.

Activity Prediction of Some Nontested Anticancer Compounds Using GA‐Based PLS Regression Models

This study is an attempt to formulate 3D quantitative structure-activity relationship (3D-QSAR) model for 6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one compounds based on computed molecular descriptors. Molecular field analysis technique has been employed to find out specific contribution of structural features such as steric, electrostatic, and hydrophobic fields of these compounds showing anticancer activities by the inhibition of epidermal growth factor kinase. Three-dimensional QSAR model is developed based on the training set using genetic algorithm feature selection combined with partial least square method. The training model is then used to predict the biological activities of some similar class of compounds which were synthesized only, but the activities were not tested. An accuracy of activity prediction has been cross-checked by introducing a new way of QSAR model validation approach utilizing random normalization correction procedure in the data set.