Virtual screening using machine learning approach
11 Apr 2013-pp 594-599
TL;DR: Modelled 3-D structure of target protein and their newly designed leads (inhibitors) are used for molecular docking studies using Hex 5.1.2 and can thereby serve as pharmacophore for the designing of potential drugs against diseases.
Abstract: In this study, potential inhibitors against Harpin protein (Pectobacterium carotovorum), and Single- stranded DNA binding protein (Pseudomonas aeruginosa) is to be found. Modelled 3-D structure of target protein and their newly designed leads (inhibitors) are used for molecular docking studies using Hex 5.1. For machine learning approach, three data sets of leads are to be formed i.e. training, dependent test and independent test and their respective physiological descriptors are identified. For virtual screening of these leads RapidMiner 5.2.002 will be used. The support vector machine (SVM) application of this software (LibSVM), is used to make a model of training data set which will further be used to check the activity of the test data set. After this, the active leads will be considered as potential inhibitors against our target proteins. This study can thereby serve as pharmacophore for the designing of potential drugs against diseases.
Citations
More filters
TL;DR: The identified mRNAs and microRNAs were validated as prognostic factors of BC disease progression, and could potentially facilitate the implementation of assays for laboratory validation, due to their reduced number.
Abstract: Defining the aggressiveness and growth rate of a malignant cell population is a key step in the clinical approach to treating tumor disease. The correct grading of breast cancer (BC) is a fundamental part in determining the appropriate treatment. Biological variables can make it difficult to elucidate the mechanisms underlying BC development. To identify potential markers that can be used for BC classification, we analyzed mRNAs expression profiles, gene copy numbers, microRNAs expression and their association with tumor grade in BC microarray-derived datasets. From mRNA expression results, we found that grade 2 BC is most likely a mixture of grade 1 and grade 3 that have been misclassified, being described by the gene signature of either grade 1 or grade 3. We assessed the potential of the new approach of integrating mRNA expression profile, copy number alterations, and microRNA expression levels to select a limited number of genomic BC biomarkers. The combination of mRNA profile analysis and copy number data with microRNA expression levels led to the identification of two gene signatures of 42 and 4 altered genes (FOXM1, KPNA4, H2AFV and DDX19A) respectively, the latter obtained through a meta-analytical procedure. The 42-based gene signature identifies 4 classes of up- or down-regulated microRNAs (17 microRNAs) and of their 17 target mRNA, and the 4-based genes signature identified 4 microRNAs (Hsa-miR-320d, Hsa-miR-139-5p, Hsa-miR-567 and Hsa-let-7c). These results are discussed from a biological point of view with respect to pathological features of BC. Our identified mRNAs and microRNAs were validated as prognostic factors of BC disease progression, and could potentially facilitate the implementation of assays for laboratory validation, due to their reduced number.
58 citations
References
More filters
TL;DR: The docking field has come of age, and the time is ripe to present the principles of docking, reviewing the current state of the field from both the computational and the biological points of view.
Abstract: The docking field has come of age. The time is ripe to present the principles of docking, reviewing the current state of the field. Two reasons are largely responsible for the maturity of the computational docking area. First, the early optimism that the very presence of the "correct" native conformation within the list of predicted docked conformations signals a near solution to the docking problem, has been replaced by the stark realization of the extreme difficulty of the next scoring/ranking step. Second, in the last couple of years more realistic approaches to handling molecular flexibility in docking schemes have emerged. As in folding, these derive from concepts abstracted from statistical mechanics, namely, populations. Docking and folding are interrelated. From the purely physical standpoint, binding and folding are analogous processes, with similar underlying principles. Computationally, the tools developed for docking will be tremendously useful for folding. For large, multidomain proteins, domain docking is probably the only rational way, mimicking the hierarchical nature of protein folding. The complexity of the problem is huge. Here we divide the computational docking problem into its two separate components. As in folding, solving the docking problem involves efficient search (and matching) algorithms, which cover the relevant conformational space, and selective scoring functions, which are both efficient and effectively discriminate between native and non-native solutions. It is universally recognized that docking of drugs is immensely important. However, protein-protein docking is equally so, relating to recognition, cellular pathways, and macromolecular assemblies. Proteins function when they are bound to other molecules. Consequently, we present the review from both the computational and the biological points of view. Although large, it covers only partially the extensive body of literature, relating to small (drug) and to large protein-protein molecule docking, to rigid and to flexible. Unfortunately, when reviewing these, a major difficulty in assessing the results is the non-uniformity in the formats in which they are presented in the literature. Consequently, we further propose a way to rectify it here.
1,251 citations
TL;DR: As an orally active, broad spectrum and potent antibacterial drug, ciprofloxacin offers a valuable alternative to broad spectrum parenterally administered antibacterial drugs for use in a wide range of clinical infections, including difficult infections due to multiresistant pathogens.
Abstract: Ciprofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. The primary mechanism of action of ciprofloxacin is inhibition of bacterial DNA gyrase. It is a broad spectrum antibacterial drug to which most Gram-negative bacteria are highly susceptible in vitro and many Gram-positive bacteria are susceptible or moderately susceptible. Unlike most broad spectrum antibacterial drugs, ciprofloxacin is effective after oral or intravenous administration. Ciprofloxacin has been most extensively studied following oral administration. It attains concentrations in most tissues and body fluids which are at least equivalent to the minimum inhibitory concentration designated as the breakpoint for bacterial susceptibility in vitro. The results of clinical trials with orally and intravenously administered ciprofloxacin have confirmed the potential for its use in a wide range of infections, which was suggested by its in vitro antibacterial and pharmacokinetic profiles. It has proven an effective treatment for many types of systemic infections as well as for both acute and chronic infections of the urinary tract. Ciprofloxacin generally appeared to be at least as effective as alternative orally administered antibacterial drugs in the indications in which they were compared, and in some indications, to parenterally administered antibacterial therapy. However, further studies are needed to fully clarify the comparative efficacy of ciprofloxacin and standard antibacterial therapies. Bacterial resistance to ciprofloxacin develops infrequently, both in vitro and clinically, except in the setting of pseudomonal respiratory tract infections in cystic fibrosis patients. The drug is also well tolerated. Thus, as an orally active, broad spectrum and potent antibacterial drug, ciprofloxacin offers a valuable alternative to broad spectrum parenterally administered antibacterial drugs for use in a wide range of clinical infections, including difficult infections due to multiresistant pathogens.
686 citations
TL;DR: This article describes and reviews the efforts using Hex 3.1 to predict the docking modes of the seven target protein–protein complexes presented in the CAPRI (Critical Assessment of Predicted Interactions) blind docking trial, and describes several enhancements to the original spherical polar Fourier docking correlation algorithm.
Abstract: This article describes and reviews our efforts using Hex 3.1 to predict the docking modes of the seven target protein-protein complexes presented in the CAPRI (Critical Assessment of Predicted Interactions) blind docking trial. For each target, the structure of at least one of the docking partners was given in its unbound form, and several of the targets involved large multimeric structures (e.g., Lactobacillus HPr kinase, hemagglutinin, bovine rotavirus VP6). Here we describe several enhancements to our original spherical polar Fourier docking correlation algorithm. For example, a novel surface sphere smothering algorithm is introduced to generate multiple local coordinate systems around the surface of a large receptor molecule, which may be used to define a small number of initial ligand-docking orientations distributed over the receptor surface. High-resolution spherical polar docking correlations are performed over the resulting receptor surface patches, and candidate docking solutions are refined by using a novel soft molecular mechanics energy minimization procedure. Overall, this approach identified two good solutions at rank 5 or less for two of the seven CAPRI complexes. Subsequent analysis of our results shows that Hex 3.1 is able to place good solutions within a list of
210 citations
TL;DR: A number of compounds are reported which are capable of restoring the phenotype to a HSL negative mutant but at higher concentrations than HSL.
Abstract: N-(3-Oxohexanoyl)-L-homoserine lactone (HSL) (I) is the autoregulator controlling carbapenem antibiotic biosynthesis in Erwinia carotovora ATCC 39048. The chemical synthesis and biological evaluation of analogues of HSL are described. These include alterations of chirality, side-chain modifications, ring size and ring hetero atom. A number of compounds are reported which are capable of restoring the phenotype to a HSL negative mutant but at higher concentrations than HSL. A-factor, the autoregulator of streptomycin biosynthesis in Streptomyces griseus, was not active as an inducer of carbapenem biosynthesis in E. carotovora.
207 citations
TL;DR: The influence of dosing intervals on the activity of gentamicin and ticarcillin against Pseudomonas aeruginosa was studied in vivo as mentioned in this paper, and the dosing schedule of Gentamicin-ticarcillin was found to significantly affect the antibacterial activity.
Abstract: The influence of dosing intervals on the activity of gentamicin and ticarcillin against Pseudomonas aeruginosa was studied in vivo. Granulocytopenic mice infected with P. aeruginosa in the thigh muscle were treated with 1-hr or 3-hr injections of gentamicin, ticarcillin, or gentamicin-ticarcillin. Plasma pharmacokinetics of the drugs were correlated with antibacterial activity. Gentamicin injected every 1 hr tended to be less active than gentamicin injected at longer intervals. In contrast, ticarcillin given every 1 hr was significantly more efficacious than equivalent total doses injected every 3 hr. The dosing schedule of gentamicin-ticarcillin was again important for ticarcillin but did not appreciably affect the antibacterial activity of gentamicin. Thus, antimicrobial chemotherapy of P. aeruginosa infections in the granulocytopenic host might be improved by administering ticarcillin rather than gentamicin as a constant infusion. The optimal antibiotic treatment of gram-negative bacterial infections in granulocytopenic patients remains an unsolved clinical problem, particularly for infections due to Pseudomonas aeruginosa, although progress has been made by combining antipseudomonal drugs and by using doses approaching toxic levels. Additional progress could possibly be made by finding optimal dosing schedules for these drugs. This aspect of antimicrobial chemotherapy has hardly been investigated. In some recent clinical trials aminoglycoside antibiotics were administered as constant
144 citations