An inverse docking approach for identifying new potential anti-cancer targets

Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA-1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified in silico should be experimentally screened for their ability to inhibit cancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce the viability of BT-474 and T47-D breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of p53 to DNA in BT-474 cells (which express mutant p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation.     

药物SAHA的潜在靶标预测及分子对接研究

利用PharmMapper的反向药效团匹配方法对SAHA(伏立诺他)的潜在靶标进行筛选,虚拟筛选得到的HDLP,HDAC8等9个靶标已被实验研究证实。靶标所涉及的疾病与实验报道的SAHA的药理学活性一致,如抗癌、抗炎、抗肿瘤等作用。另外,预测出与老年痴呆、糖尿病、风湿性关节炎等疾病相关的SAHA的潜在靶标,进而利用分子对接技术对SAHA与潜在靶标的作用模式进行了研究。SAHA与潜在靶标的对接结果表明,它们在形状、电负性和疏水性方面匹配良好,能有效抑制靶标的活性。本实验研究表明,反药效团匹配和分子对接方法可作为预测药物潜在靶标的有效手段,为SAHA新的适用症的进一步研究提供理论指导。     

Prediction of membrane protein orientation in lipid bilayers: a theoretical approach.

Over the past few years, several three-dimensional (3-D) structures of membrane proteins have been described with increasing accuracy, but their relationship with membranes are still not well understood. Recently, we have developed an empirical method, Integral Membrane Protein and Lipid Association (IMPALA), to predict the insertion of molecules (lipids, drugs) into lipid bilayers (Proteins 30 (1998) 357). The IMPALA uses a Monte Carlo minimisation procedure to calculate the depth and the angle of insertion of membrane-interacting molecules taking into account the restraints dictated by a lipid bilayer. In this paper, we use IMPALA to test the insertion of 23 integral membranous proteins (IMPs) and 2 soluble proteins into membranes. Four IMP are studied in detail: OmpA, maltoporin, MsCl channel and bacteriorhodopsin. The 3-D structures of the proteins are kept constant and the insertion into membrane is monitored by minimising the value of the restraint representing the sum of two terms, one for lipid perturbation and the other for hydrophobicity. The two soluble proteins are rejected from the membrane whereas, under the same conditions, all the membrane proteins remain inside, if the solvent accessible surface of the amino acids located inside the pore of porins is ignored. The results give the tilt angle of the IMP helices or strands with respect to the membrane surface and the depth of the protein mass centre insertion. We conclude that the restraint terms of IMPALA could be used to study the insertion of model structures or complexes of proteins within membranes.     

Detection of metallic and nonmetallic concealed targets based on millimeter‐wave inverse scattering approach

A millimeter‐wave radar based on active invers scattering approach for two dimensional screening of metallic and nonmetallic concealed targets is presented. The perceived challenges of detecting a nonmetallic target exhibiting poor dynamic range for measurement systems are analyzed and discussed by comparing the performance of three different antenna sensors. A short time duration pulse with frequency sweep covering 27 to 33 GHz band is used to feed the antenna sensors. In our experimental test, we buried a concealed target consists of metallic or dielectric strips under a dielectric layer that simulates the human body model. Waveguide and printed antipodal Vivaldi antennas are considered to study the target detectability and the quality of the measured millimeter‐wave images. The use of proposed AVA resulted in a better‐quality image with lower noise effect for both metallic and nonmetallic cases.     

In silico molecular docking studies of new potential 4-phthalazinyl-hydrazones on selected Trypanosoma cruzi and Leishmania enzyme targets

Recently, a series of 4-phthalazinyl-hydrazones under its E-configuration have exhibited excellent in vitro antichagasic and antileishmanial profiles. Preliminary assays on both parasites suggested that the most active derivatives act through oxidative and nitrosative stress mechanisms; however, their exact mode of actions as anti-trypanosomal and anti-leishmanial agents have not been completely elucidated. This motivated to perform a molecular docking study on essential trypanosomatid enzymes such as superoxide dismutase (SOD), trypanothione reductase (TryR), cysteine-protease (CP) and pteridine reductase 1 (PTR1). In addition, to understand the experimental results of nitric oxide production obtained for infected macrophages with Leishmania parasite, a molecular docking was evaluated on nitric oxide synthase (iNOS) enzyme of Rattus norvegicus. Both diastereomers (E and Z) of the 4-phthalazinyl-hydrazones were docked on the mentioned targets. In general, molecular docking on T. cruzi enzymes revealed that the E-diastereomers exhibited lower binding energies than Z-diastereomers on the Fe-SOD and CP enzymes, while Z-diastereomers showed lower docking energies than E-isomers on TryR enzyme. For the Leishmania docking studies, the Z-isomers exhibited the best binding affinities on the PTR1 and iNOS enzymes, while the TryR enzyme showed a minor dependence with the stereoselectivity of the tested phthalazines. However, either the structural information of the ligand-enzyme complexes or the experimental data suggest that the significant antitrypanosomatid activity of the most active derivatives is not associated to the inhibition of the SOD, CP and PTR1 enzymes, while the TryR inhibition and nitric oxide generation in host cells emerge as interesting antitrypanosomatid therapeutic targets.     

Identification and validation of calmodulin as a binding protein of an anti-proliferative small molecule 3,4-dihydroisoquinolinium salt

IHY-153 (2-(2,5-difluorobenzyl)-3,4-dihydro-5-(10-hydroxydecyl)-6-methoxy-1-undecylisoquinolinium bromide) was recently discovered as a small molecule that potently inhibits proliferation of tumor cells by inducing cell-cycle arrest at G0-G1 phase. To investigate the basis of anti-proliferative activity of IHY-153, cellular binding proteins of biotinyl-IHY-153 were screened using T7 phage displayed human cDNA libraries. Calmodulin-expressing phage specifically bound to immobilized IHY-153 in a Ca(2+) -dependent manner. The interaction between IHY-153 and Ca(2+) /CaM was validated through phage competition binding assays, surface plasmon resonance analysis, and molecular modeling. IHY-153 induced sustained phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and subsequently increased p21(WAF1) expression in colon cancer cells. These results demonstrate that IHY-153, a novel small molecule, targets Ca(2+) /CaM and indicate that this compound functions as an anti-proliferative agent by influencing Ca(2+) /CaM-dependent signal transduction.     

An improved approach to the inverse dynamic analysis of parallel manipulators by a given virtual screw

This paper provides an improved approach to the inverse dynamic analysis of parallel manipulators (PMs) based on the screw theory and Jourdain’s principle of virtual power. First, velocity and acceleration mappings from the Cartesian coordinate system to the screw system are established. Next, by introducing a novel concept of virtual screw that is formulated by a combination of virtual angular velocity and virtual linear velocity, four theorems are defined and proven to build the dynamic equations of PMs. Owing to the existing expression of acceleration screws and the introduced virtual screw, the proposed approach not only has the advantages of intuitive physical concepts and universal form but also avoids the difficult derivatives of time and the determination of generalized velocities, which is employed by conventional methods and is determined difficultly for some hybrid PMs. Finally, taking a 1PU?+?3UPS PM as an instance, the inverse dynamic analysis and numerical examples are presented to demonstrate the feasibility of the proposed approach.     

Algorithms for the inverse and a generalization of the state space approach to finite automata

The inverse of the state space approach to finite automata is developed. Both the obverse and converse aspects of the state space approach are extended to the general case in which the alphabet of a finite automaton consists of 2 ^m symbols wherem is any positive integer. Relevant algorithms are designed and analyzed. State equations having or not having rational-function solutions are investigated and discussed.     

Exploring the potential of complex formation between a mutant DNA and the wild type protein counterpart: a MM and MD simulation approach

We have demonstrated that the methods of molecular modeling and molecular dynamics simulation might be used to assess whether a specific mutation in the DNA would destabilize a known DNA-protein complex. The approach is based on probing the changes in the interaction that would be induced into the complex if within the already formed wild type complex the mutation could be introduced. We have used Hoxc8-DNA complex as a test system where it is known that the Hoxc8 binding affinity of the DNA is completely lost upon mutation of the DNA by replacing TAAT stretch to GCCG. Mutation was obtained by changing the relevant base pairs into the DNA of the model of the corresponding wild type complex developed by homology modeling and MD simulation in water for 2.0 ns. Comparison of the structure, dynamics and interactions between the hypothetical mutant model with those of the similarly refined wild type model shows that the loss of affinity of the mutant DNA to Hoxc8 has two different origins: (i) loss of several strong H-bonds as the direct consequences of mutation and (ii) reduced H-bonds in the common parts due to a net loss or inferior H-bonding geometry induced by the mutation as indirect effects. The net change in the interaction energy between the DNA and the protein in the best possible configuration indicated the experimentally observed destabilization effects. No significant change in the groove width was observed and no correlation was found between the water-bridges and the loss of affinity.     

Comparison of RBF and MLP neural networks to solve inverse kinematic problem for 6R serial robot by a fusion approach

In this paper, a fusion approach to determine inverse kinematics solutions of a six degree of freedom serial robot is proposed. The proposed approach makes use of radial basis function neural network for prediction of incremental joint angles which in turn are transformed into absolute joint angles with the assistance of forward kinematics relations. In this approach, forward kinematics relations of robot are used to obtain the data for training of neural network as well to estimate the deviation of predicted inverse kinematics solution from the desired solution. The effectiveness of the fusion process is shown by comparing the inverse kinematics solutions obtained for an end-effector of industrial robot moving along a specified path with the solutions obtained from conventional neural network approaches as well as iterative technique. The prominent features of the fusion process include the accurate prediction of inverse kinematics solutions with less computational time apart from the generation of training data for neural network with forward kinematics relations of the robot.     

分子局部图形绘制及电势分析软件设计与实现

随着计算机技术的迅速发展,分子图形学在研究分子结构、计算机辅助分子设计中发挥着日益显著的作用.本文作者利用Visual C#呈序设计语言,结合已有的Raswin和WaferPainter两个开源软件,通过对.PDB(蛋白质数据库)文件、原子电量数据文件的读取、分析和计算,改进了原有软件仅限于观看分子的整体结构、绘制整体三维静电势、无法根据用户需要显示局部细节及二维静电势图的缺陷,实现了在用户定制的坐标范围内完成局部分子图、分子的平面静电势图的绘制等功能,这在蛋白质分子结构研究、分析原子间的作用力以及辅助分子设计方面有着重要意义.     

Distributions of electrostatic potentials and forces in a DNA molecule by a concentric cylindrical model. II. Effects of the Debye-Huckel parameter

We have developed a mathematical method to compute the three-dimensional distributions of potentials, circumferential forces, and electrostatic free energy in a DNA molecule. A DNA molecule was described by a three-layered concentric cylinder. For geometric reasons, discrete point phosphate charges are arranged helically around the central axis of the DNA in equivocal circumferential steps. The Debye-Huckel theory was applied to linearize the Poisson-Boltzmann equation and obtain analytical solutions. As the value of the Debye-Huckel parameter κ increased, the potentials in the inner region increased, and the reaction potentials and the middle-region potentials decreased. Forces in the inner, middle, and outer regions decreased, while the reaction force increased. The influence of the Debye-Huckel parameter strongly depended on the radial position of the DNA. Changes in the dielectrical constant of the middle region had a significant influence on the electrostatic energy of the DNA. This method will be useful for evaluating the interaction between the physiological ionic circumstances around DNA, the ion adsorption, and the melting process of the DNA double strand. This work was presented, in part, at the Sixth International Symposium on Artificial Life and Robotics, Tokyo, Japan, January 15–17, 2001     

Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking,molecular dynamic simulation and virtual screening

Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold.     

Kalman filtering: a new approach for building global approximations. Application to the inverse optimization of an explosively formed penetrator (EFP)

As the use of approximations is often the only way to deal with the optimization of complex structures, this paper discusses the use of Kalman filtering as a new approach for building global approximations. Basic ideas and procedures of Kalman filters are first recalled. Next, key elements of how to implement the method for design problems are described. Finally, in order to evaluate the performance of the approach, an inverse problem which consists in optimizing a warhead with respect to constraints on the resulting projectile is studied. It is shown that global approximations are convenient for the solution of complex optimization problems and that Kalman filtering techniques appear to be an interesting strategy for the construction of global approximations in structural optimization.     

Prediction of interface yield stress and plastic viscosity of fresh concrete using a hybrid machine learning approach

The interface yield stress and the plastic viscosity of concrete mixes critically influence their pumpability. This study constructs and verifies a data-driven method for predicting these two important parameters. The proposed method is a hybridization of Least Squares Support Vector Machine (LSSVM) and Particle Swarm Optimization (PSO). The LSSVM is employed to infer the mapping function between the two concrete mix’s parameters and their influencing factors. Moreover, in order to overcome the challenging task of fine-tuning the LSSVM model hyper-parameters, the PSO algorithm, a swarm intelligence based metaheuristic, is utilized to optimize the LSSVM prediction model. A data set including 142 experimental tests has been collected in this study to construct and verify the proposed hybrid method. Experimental results supported by the Wilcoxon signed-rank test point out that the hybridization of LSSVM and PSO (with coefficients of determination = 0.71 and 0.77 for interface yield stress and plastic viscosity predictions, respectively) can deliver predictive results superior to those of benchmark models. Hence, the hybrid model of PSO and LSSVM can be a promising alternative to assist engineers in the task of concrete structure construction.