Search results for "Simulation."
showing 10 items of 4779 documents
Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection
2021
The identification of chemical compounds able to bind specific sites of the human/viral proteins involved in the SARS-CoV-2 infection cycle is a prerequisite to design effective antiviral drugs. Here we conduct a molecular dynamics study with the aim to assess the interactions of ivermectin, an antiparasitic drug with broad-spectrum antiviral activity, with the human Angiotensin-Converting Enzyme 2 (ACE2), the viral 3CLpro and PLpro proteases, and the viral SARS Unique Domain (SUD). The drug/target interactions have been characterized in silico by describing the nature of the non-covalent interactions found and by measuring the extent of their time duration along the MD simulation. Results …
Frontiers of metal-coordinating drug design
2020
INTRODUCTION: The occurrence of metal ions in biomolecules is required to exert vital cellular functions. Metal-containing biomolecules can be modulated by small-molecule inhibitors targeting their metal-moiety. As well, the discovery of cisplatin ushered the rational discovery of metal-containing-drugs. The use of both drug types exploiting metal–ligand interactions is well established to treat distinct pathologies. Therefore, characterizing and leveraging metal-coordinating drugs is a pivotal, yet challenging, part of medicinal chemistry. AREA COVERED: Atomic-level simulations are increasingly employed to overcome the challenges met by traditional drug-discovery approaches and to compleme…
The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC
2013
The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given…
Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum
2012
Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19-46, 108-134 and 140-163. The regions covered by these residues are know…
Modeling Drug Effects on Personalized 3D Models of the Heart: A Simulation Study
2010
[EN] The use of anti-arrhythmic drugs is common to treat heart rhythm disorders. Computational modeling and simulation are powerful tools that can be used to investigate the effects of specific drugs on cardiac electrophysiology. In this work a patient-specific anatomical heart model is built to study the effects of dofetilide, a drug that affects IKr current in cardiac cells. We study the multi-scale effects of the drug, from cellular to organ level, by simulating electrical propagation on tissue coupled cellular ion kinetics for several heart beats. Different cell populations configurations namely endocardial, midmyocardial and epicardial are used to test the effect of tissue heterogeneit…
Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay
2014
The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination c…
A Branch-and-Cut method for the Capacitated Location-Routing Problem
2011
International audience; Recent researches in the design of logistic networks have shown that the overall distribution cost may be excessive if routing decisions are ignored when locating depots. The Location-Routing Problem (LRP) overcomes this drawback by simultaneously tackling location and routing decisions. The aim of this paper is to propose an exact approach based on a Branch-and-Cut algorithm for solving the LRP with capacity constraints on depots and vehicles. The proposed method is based on a zero-one linear model strengthened by new families of valid inequalities. The computational evaluation on three sets of instances (34 instances in total), with 5–10 potential depots and 20–88 …
SIMULATION AND EXPERIMENTAL METHODS FOR IMPROVING ENERGY EFFICIENCY, ENVIRONMENTAL PERFORMANCE AND RESILIENCE OF SINGLE AND CLUSTERED GROUPS OF BUILD…
2021
Energy consumption in the building sector is responsible for 36% of the energy use worldwide (corresponding to 39% of the total energy-related CO2 emissions), while at the European level the building sector accounts for a share of the total energy consumption comprised between 25% and 40% (corresponding to about 35% of the overall CO2 emissions throughout Europe). Concerning the Italian context, instead, such figures stand at about 40% and 17.5% for the energy consumption and for the CO2 emissions, respectively. In light of this, much attention has been paid, at global, European and single countries (national) levels on the important aspects regarding the reduction of energy consumption and…
Mode-superposition correction method for deterministic and stochastic analysis of structural systems
2001
The role played by the modal analysis in the framework of structural dynamics is fundamental from both deterministic and stochastic point of view. However the accuracy obtained by means of the classical modal analysis is not always satisfactory. Therefore it is clear the importance of methods able to correct the modal response in such a way to obtain the required accuracy. Many methods have been proposed in the last years but they are meaningful only when the forcing function is expressed by an analytical function. Moreover in stochastic analysis they fail for white noise excitation. In the paper a method able to give a very accurate response for both deterministic and stochastic input is p…
Inferring slowly-changing dynamic gene-regulatory networks
2015
Dynamic gene-regulatory networks are complex since the interaction patterns between their components mean that it is impossible to study parts of the network in separation. This holistic character of gene-regulatory networks poses a real challenge to any type of modelling. Graphical models are a class of models that connect the network with a conditional independence relationships between random variables. By interpreting these random variables as gene activities and the conditional independence relationships as functional non-relatedness, graphical models have been used to describe gene-regulatory networks. Whereas the literature has been focused on static networks, most time-course experi…