Search results for "modeling"

Development and optimisation of computational tools for drug discovery

The aim of my PhD project was the development, optimisation, and implementation of new in silico virtual screening protocols. Specifically, this thesis manuscript is divided into three main parts, presenting some of the papers published during my doctoral work. The first one, here named CHEMOMETRIC PROTOCOLS IN DRUG DISCOVERY, is about the optimisation and application of an in house developed chemometric protocol. This part has been entirely developed at the University of Palermo - STEBICEF Department - under the guide of my supervisors. During the development of this part I have personally worked on the tuning and optimisation of the algorithm and on the docking campaigns to obtain molecul…

Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.

2010

Apicomplexan parasites encompass several human- and animal-pathogenic protozoans such as Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin-dependent kinases (CDKs) are key molecules in cell-cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK-like proteins, of which one—E. tenella CDK-related kinase 2 (EtCRK2)—has already been charact…

Complete Sequence of the 24-mer Hemocyanin of the TarantulaEurypelma californicum

2000

Hemocyanins are large oligomeric respiratory proteins found in many arthropods and molluscs. The hemocyanin of the tarantula Eurypelma californicum is a 24-mer protein complex with molecular mass of 1,726,459 Da that consists of seven different polypeptides (a–g), each occupying a distinct position within the native molecule. Here we report the complete molecular structure of the E. californicumhemocyanin as deduced from the corresponding cDNAs. This represents the first complex arthropod hemocyanin to be completely sequenced. The different subunits display 52–66% amino acid sequence identity. Within the subunits, the central domain, which bears the active center with the copper-binding sit…

Suitability ofMMGBSAfor the selection of correct ligand binding modes from docking results

2018

The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (a) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (b) improved the correlation coefficient of computational and experimental results of rescor…

Grafting TRAIL through Either Amino or Carboxylic Groups onto Maghemite Nanoparticles: Influence on Pro-Apoptotic Efficiency

2021

International audience; Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine superfamily. TRAIL is able to induce apoptosis through engagement of its death receptors DR4 and DR5 in a wide variety of tumor cells while sparing vital normal cells. This makes it a promising agent for cancer therapy. Here, we present two different ways of covalently grafting TRAIL onto maghemite nanoparticles (NPs): (a) by using carboxylic acid groups of the protein to graft it onto maghemite NPs previously functionalized with amino groups, and (b) by using the amino functions of the protein to graft it onto NPs functionalized with carboxylic acid groups. The two …

Molecular modeling studies on dopamine-amino acid conjugates as potential dopaminergic modulators

2015

Scatter Search—Wellsprings and Challenges

2006

I came up with the idea of editing this volume in the summer of 2002 while working on the book "Scatter search methodologies and implementations in C" with Manuel Laguna in the University of Colorado at Boulder. There, Fred Glover kindly let me use his office, where I found a copy of the "Tabu Search Methods for Optimization" special issue that he edited in 1988 for the European Journal of Operational Research. This encounter made me realize that Scatter Search has reached a level of maturity as an optimization method that has parallels with what Tabu Search was experiencing in the late eighties. So I thought that the moment was perfect to embark on this project, which has been supported en…

Potential of the EPA/DHA 6/1 formulation to prevent endothelial dysfunction and cardiopulmonary remodeling in pulmonary arterial hypertension in rats

2016

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure. Pulmonary endothelial dysfunction, inflammation and oxidative stress promote the development of pulmonary hypertension. Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have been shown to protect the cardiovascular system and reduce inflammation and oxidative stress. The present study evaluate the potential of EPA:DHA 6:1 to prevent monocrotaline-induced PAH in rats. EPA:DHA 6:1 treatment (500 mg/kg/d, p.o) prevented the MCT-induced mean pul…

A modelling population-based approach to the effect of granulocyte growth factors during chemotherapy-induced neutropenia

2020

The work of this thesis is based on results of a cohort study whose main objective was to define the optimal schedule of prophylactic administration of granulocyte growth factors (G-CSF) in the context of FOLFIRINOX treatment. For this purpose, a pharmacokinetic/pharmacodynamic (PK/PD) model was built to describe the absolute neutrophil counts (ANC) time course in our population, including the three chemotherapies neutropenic effect, but also the stimulating effect of exogenous G-CSF on the proliferation and maturation of neutrophils. Based on the estimates of the model parameters, simulations were performed to determine the incidence and duration of neutropenia for each prophylactic G-CSF …

Selecting ribosomal protein genes for invertebrate phylogenetic inferences: how many genes to resolve the Mollusca?

2010

Summary 1. Multi-gene analyses are currently the gold standard in phylogenetics, despite limited taxon sampling. To facilitate broad taxon representation on an economically tolerable level, we optimize the gene selection for future PCR-based sampling strategies. 2. Highly expressed ribosomal proteins (RP) were sampled chiefly for molluscs, the second largest metazoan phylum with largely unknown internal relationships. Thirty-two new sequences for Lepidochitona cinerea (Polyplacophora) were integrated into a data-matrix of 79 RP genes, comprising 16 mollusc species (five classes). The resulting maximum likelihood tree was used to evaluate each single-gene tree according to its topological fi…