Silico Experiments Research Articles

Translocation Processes of Pt(II)-Based Drugs through Human Breast Cancer Cell Membrane: In Silico Experiments.

Breast cancer is one of the most frequent modalities of cancer worldwide, with notable mortality. The medication based on platinum drugs (cisplatin (cddp), carboplatin (cpx), and oxaliplatin (oxa)) is a conventional chemotherapy despite severe side effects and the development of drug resistance. In order to provide a deeper molecular description of the influx and efflux processes of platinum drugs through breast cancer tissues, this study focuses on molecular dynamics (MD) simulations of the passive translocation process through a realistic plasma membrane prototype of human breast cancer cell (c_memb). The results showed that the permeation events were mainly mediated by neutral lipids (DOPC, DOPE, and cholesterol), producing a low and temporary membrane deformation. The drug insertion in the region of polar heads was the most favorable stage of the translocation mechanism, especially for cddp and oxa with potential wells of -8.6 and -9.8 kcal mol-1, respectively. However, the potentials of mean force (PMF) revealed unfavorable kinetics for the permeation of these drugs through lipid tails, with energy barriers of 28.3 (cddp), 32.2 (cpx), and 30.4 kcal mol-1 (oxa). The low permeability coefficients (P) of cpx and oxa, which were 3 and 1 orders of magnitude inferior than for cddp, resulted from the high energy barriers for their traslocation processes through the membrane. The obtained results provide a more accurate picture of the permeation of Pt(II)-based drugs through breast cancer cells, which may be relevant for the design and evaluation of new platinum complexes.

In Silico Experiments to Explore the Heating Efficiency of Magnetic Nanoparticles in Hyperthermia Preclinical Tests

AbstractPreclinical tests on murine models are typically performed to evaluate the therapeutic efficacy of novel magnetic nanoparticles (MNPs) in cancer treatment with magnetic hyperthermia. Here, through in silico experiments, in vivo tests are mimicked on a 30 g mouse and a 500 g rat, with the aim of determining the optimal treatment conditions allowing to reach the therapeutic temperature range (40−45 °C) within tumor regions. Various types of MNPs are considered with very different heating properties in terms of specific loss power, varying their administered dose, as well as the frequency and peak amplitude of the magnetic field. The analysis is performed by means of finite element models that solve the low‐frequency electromagnetic (EM) field problem and the Pennes’ bioheat transfer equation, to calculate the temperature increase in biological tissues due to the combined effects of EM field exposure and MNP activation. The methodology, which can be generalized to any type of MNPs, has permitted to identify the proper doses of MNPs to be administered to the tumor region, as a function of their heating properties and magnetic field parameters, highlighting the conditions that can lead to possible overheating, generation of hot spots or magnetic hyperthermia inefficacy.

ANISE: an application to design mechanobiology simulations of planar epithelia.

TiFoSi (Tissues Forces & Signaling) is an efficient computational tool for performing mechanobiology simulations of planar epithelia. A drawback of this tool is that it relies on an XML configuration file (input data) that can be cumbersome to set up and/or decode due to the endless possibilities of the software. Moreover, some modeling know-how is needed in order to provide equations that describe gene regulatory interactions. These factors limit the usability of this tool for users with a weak computational and/or mathematical background. Here, we introduce ANISE (grAphical coNfigurator of TiFoSi In Silico Experiments), a web-app that allows to easily setup the configuration of mechanobiology simulations using TiFoSi. The application covers all the configuration modules in TiFoSi comprehensively (from basic to advanced editing options) and uses a graphical approach (e.g. to build the modeling equations of gene regulatory networks). http://github.com/lsym-uveg/anise (server: http://lsymserver.uv.es/lsym/ANISE).

Vertically Aligned Carbon Nanotubes for Monovalent Cation Selective Membranes Designed by in Silico Experiments

Vertically Aligned Carbon Nanotubes for Monovalent Cation Selective Membranes Designed by in Silico Experiments

In Silico Experiments to Explore Metabolic Bone Diseases and Their Drug Treatment

In Silico Experiments to Explore Metabolic Bone Diseases and Their Drug Treatment

In Silico Experiments as a Method to Compare Transportes Mechanism

Sodium-mediated solute transporters (SLC5 Family) translocate their substrates using sodium gradient as driving force. These transporters are found in diverse fields of life, and have the unique ability to harness the energy stored in ionic gradients to accumulate small molecules essential for life, as well as expelling toxins and other harmful compounds. Unfortunately, there is no precise experimental structural information on many of the sodium-dependent transporters. Therefore, taking advantage of the versatility of the experiments in Silico, it is possible to develop computational studies that aim to reveal and examine regions and / or individual amino acids in members of this family that may be important for the binding or translocation of substrates and Na +, as well as elucidating the effect of amino acid substitutions on affinity, changes in stoichiometry, and the activity of study proteins, which may provide guidelines for the study of future therapeutic targets. In the present study, the changes of the global movements of the native form of three proteins of the SLC5 family in the presence and absence of the substrates translocating the transporter were compared from computational point of view, applying Normal Modes Analysis using the model of Anisotropic Network (ANM), which has proved to be an useful computational method for predicting membrane protein dynamics and has been shown to be consistent with experimental data in terms of the forms and mechanisms of membrane proteins movements.

Observational Cohort Studies and the Challenges of In Silico Experiments

Observational Cohort Studies and the Challenges of In Silico Experiments

Design of In Silico Experiments as a Tool for Nonlinear Sensitivity Analysis of Knowledge-Driven Models

We propose the in silico use of the Design of Experiments (DoE) methodology in the analysis of parametric sensitivity of a detailed process model, so that we overcome the substantial limitation of ...

A novel variant of t-PA resistant to plasminogen activator inhibitor-1; expression in CHO cells based on In Silico experiments

Resistance to PAI-1 is a factor which confers clinical benefits in thrombolytic therapy. The only US FDA approved PAI-1 resistant drug is Tenecteplase®. Deletion variants of t-PA have the advantage of fewer disulfide bonds in addition to higher plasma half lives. A new variant was developed by deletion of the first three domains in t-PA in addition to substitution of KHRR 128-131 amino acids with AAAA in truncated t-PA. The specific activity of this new variant, 570 IU/μg, was found to be similar to those found in full length t-PA (Alteplase®), 580 IU/μg. A 65% and 85% residual activity after inhibition by rPAI-1 was observed for full length and truncated-mutant form, respectively. This new variant as the first PAI-1 resistant truncated t-PA may offer more advantages in clinical conditions in which high PAI-1 levels makes the thrombolytic system prone to re-occlusion.

Expression of a Novel Chimeric Truncated t-PA in CHO Cells Based on in Silico Experiments

Tissue plasminogen activator (t-PA) is one of the fibrin-specific serine proteases that play a crucial role in the fibrinolytic system. The rapid clearance of the drug from the circulation, caused by its active uptake in the liver, has lead to complicated clinical applications. Different forms of plasminogen activators have been developed to treat thrombotic disease. Deletion of the first three domains of t-PA by gene manipulation techniques has shown a significant increase in its plasma half life. In order to compensate the disadvantage of higher bleeding risk, a novel chimeric truncated form of t-PA with 394 amino acids and more fibrin affinity compared to the truncated form was designed to be expressed in Chinese Hamster Ovarian (CHO) cells. The recombinant chimeric plasminogen activator consists of kringle 2 and serine protease (K2S) domains of t-PA, namely GHRP-SYQ-K2S. The level of expression was found to be 752 IU/ml with 566,917 IU/mg specific activity, based on amidolytic activity. The fibrin binding of this novel chimeric truncated t-PA was 86% of the full length t-PA at a fibrinogen concentration of 0.2 mg/ml. This could be a promising approach with more desirable pharmacodynamic properties compared to existing commercial forms.

Using provenance to manage knowledge of In Silico experiments

This article offers a briefing in one of the knowledge management issues of in silico experimentation in bioinformatics. Recording of the provenance of an experiment-what was done; where, how and why, etc. is an important aspect of scientific best practice that should be extended to in silico experimentation. We will do this in the context of eScience which has been part of the move of bioinformatics towards an industrial setting. Despite the computational nature of bioinformatics, these analyses are scientific and thus necessitate their own versions of typical scientific rigour. Just as recording who, what, why, when, where and how of an experiment is central to the scientific process in laboratory science, so it should be in silico science. The generation and recording of these aspects, or provenance, of an experiment are necessary knowledge management goals if we are to introduce scientific rigour into routine bioinformatics. In Silico experimental protocols should themselves be a form of managing the knowledge of how to perform bioinformatics analyses. Several systems now exist that offer support for the generation and collection of provenance information about how a particular in silico experiment was run, what results were generated, how they were generated, etc. In reviewing provenance support, we will review one of the important knowledge management issues in bioinformatics.

Special Issue: Fact Databases and Freewares] Bioinformatics Tool for Genomic Era: A Step towards the In Silico Experiments - Focused on Molecular Cloning

We are making an attempt to perform the molecular biological experiments in silico, one of the most promising alternative means of the biological experiments in vitro. Among the various fields of experiments, this paper is especially focused on molecular cloning, because DNA information is more systematically and exhaustively collected than that of other molecules. There are some advantages in in silico experiments in view of planning molecular biological experiments, usage as lab notebook, educational tool to learn molecular biological experiments. However, performing in silico cloning requires some formulations such as recording of the end shapes of digested products by restriction enzymes or amplified products by PCR. For this purpose, we introduce some extensions to GenBank/EMBL database annotation convention, and incorporate them into existing convention as new feature keys and qualifiers. In addition, features on a DNA sequence are occasionally truncated in the case of amplified products of PCR or digested fragments by restriction enzymes, therefore the annotations about the truncated features should be also formulated. The ambivalent nature of DNA requires frequent changes of the interested strand to and fro, therefore a reverse complementary operation of large size DNA is necessary to be implemented for such software. According to these definitions or data descriptions, we have developed a software tool for in silico experiments, named in silico MolecularCloning, and perform a few of typical molecular cloning experiments on computer, and verified that this approach would be effective.

Environmental Physical Modulation of Intrinsic Tendency to Growth of Multicellular Tumour Spheroids: In Silico Experiments

Lowering in nutrient local availability and rising in host mechanical rigidity are two distinct boundary conditions that affect the growth of solid a-vascular cancers in similar ways (inhibition of growth). In silico experiments based on a physical-mathematical model can shed light on some of the mechanisms at the basis of these effects and suggest that the self-organizing properties of neoplastic populations are greatly modulated by environmental restrictions.