Marco Ferrone

Computer simulation of nylon-6/organoclay nanocomposites: prediction of the binding energy

Molecular mechanics/dynamics computer simulations are used to explore the atomic scale structure and to predict binding energy values for polymer/clay nanocomposites based on nylon-6, montmorillonite (MMT) and several, different quaternary ammonium salts. Our results reveal that the energy of binding between the polymeric matrix and the montmorillonite platelet shows a decreasing trend with increasing molecular volume V of the quaternary ammonium salt used as surfactant. On the other hand, both the binding energy between the polyamide and the quat, and between the quat and the montmorillonite increase with increasing V, although with a different slope. Shorter hydrocarbonic chains are more effective in producing favorable binding energies with respect to longer ones, and the substitution of hydrogen atoms with polar groups, such as –OH or –COOH on the quaternary ammonium salt generally results in a greater interaction of the quat with the polymer. Finally, under the hypothesis that the clay platelets are uniformly dispersed within the polymer matrix, the pristine clay still yields a high interfacial strength between MMT and nylon-6.

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 μM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

T315I-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study

The early stage of chronic myeloid leukemia is triggered by the tyrosine kinase Bcr-Abl. Imatinib mesylate, a selective inhibitor of Bcr-Abl, has been successful in chronic myeloid leukemia clinical trials, but short-lived remissions are usually observed in blast crisis patients. Sequencing of the BCR-ABL gene in relapsed patients revealed a set of mutants that mediate drug resistance. Previously reported work postulated that the missense T315I mutation both alters the three-dimensional structure of the protein binding site, thus decreasing the protein sensitivity for the drug, and does not feature a fundamental hydrogen bond that is critical for binding with imatinib. These speculations, however, were not supported by investigations at the molecular modeling level. Here, we present the results obtained from the application of molecular dynamics simulations to the study of the interactions between T315I Bcr-Abl and imatinib. For the first time, we show that, with respect to the wild-type system, the absence of the supposedly critical H-bond is not the only cause for the failure of receptor inhibition by imatinib, but also a plethora of other protein/drug interactions are drastically and unfavorably changed in the mutant protein.

Host–guest inclusion complexes between anticancer drugs and β-cyclodextrin: computational studies

Abstract In this paper we analyze the possibility of forming host–guest inclusion complexes between β-cyclodextrin (BCD) and several anticancer active principles, characterized by different mechanism of action, by atomistic molecular dynamics simulations. The trajectories of the insertion angles, rotation of the non-polar parts of the drugs inside the macrocycle and other geometrical features give detailed information on the dynamics of the complexes. The relative binding energies in all cases indicate possibilities of formation of inclusion complexes between BCD and the anticancer drugs either in a 1:1 or in a 2:2 stoichiometry.

Estimation of the Binding Energy in Random Poly (Butylene terephtalate-co-thiodiethylene terephtalate) Copolyesters/Clay Nanocomposites via Molecular Simulation

Molecular mechanics/dynamics computer simulations are used to explore the atomic scale structure and to predict binding energy values for polymer/clay nanocomposites based on random poly(butylene terephtalate-co-thiodiethylene terephtalate) copolyesters, montmorillonite and several, different organic surfactant. Our results reveal that the energy of binding between the polymeric matrix and the montmorillonite platelet shows a decreasing trend with increasing molecular volume, V, of the organic compounds used as surfactant, and that the substitution of hydrogen atoms with a –SH moiety in the organic molecules results in progressively increasing interaction of the surfactant with the copolymer, as the sulfur-containing comonomer concentration is increased. Finally, under the hypothesis that the clay platelets are uniformly dispersed within the polymer matrix, the pristine clay still yields a high interfacial strength between MMT and copolymers.

Synthesis and in vitro evaluation of the anti-viral activity of N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides

A series N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides (8e-k, 9e-i, k, l) and their parent amines (5a-c and 6a-d) were prepared according to Schemes (1 and 2). Compounds were evaluated in vitro for cytotoxicity and antiviral activity against a wide spectrum of RNA (positive- and negative-sense) viruses, like [Bovine Viral Diarrhea Virus (BVDV), Yellow Fever Virus (YFV), Coxsackie Virus B (CVB-2), Polio Virus (Sb-1), Human Immunodeficiency Virus (HIV-1), Respiratory Syncytial Virus (RSV)] or double-stranded (dsRNA) virus, like Reoviridae (Reo-1). The Entero (CVB-2 and Sb-1) were the only viruses inhibited by title compounds. In particular, two of them emerged for their selective, although not very potent, antiviral activity: 8i, which was the most active against CVB-2 (CC50 >100 microM; EC50 = 10 microM) and 9l, which was the most active against Sb-1 (CC50 90 microM; EC50 = 30 microm). Title compounds were evaluated in silico against the Sb-1 helicase, as the crystal structure of this enzyme was not available, the corresponding 3D model was obtained by homology techniques (see Fig. 2).

Modern surgical therapy: limb salvage and the role of amputation for extremity soft-tissue sarcomas.

Historically the surgical management of extremity soft-tissue sarcomas (ESTS) commonly involved amputation. Nowadays limb-sparing, function-preserving surgery is the standard of care for ESTS. Adjuvant therapies such as radiation therapy and chemotherapy are used selectively in an effort to minimize both local recurrence and distant spread. Less common modalities, such as isolated limb perfusion, isolated limb infusion, and hyperthermia are being evaluated to potentially expand the cohort of individuals who may be eligible for limb-sparing surgery and to improve outcomes. This article reviews the standard and evolving approaches to the management of ESTS.

Scaling properties in the molecular structure of three-dimensional, nanosized phenylene-based dendrimers as studied by atomistic molecular dynamics simulations

Abstract Three-dimensional polyphenylene dendrimers (PDs) can be prepared in ways that enable control of their shape. Their structures may be used as scaffolds with a wide variety of functionality, enabling them to be used as functional nanoparticles with a large range of possible applications, ranging from light emitting devices to biological sensors or drug delivery tools. As PDs have been synthesized only recently, their structural and chemico-physical characterization is still in its infancy. Accordingly, in this paper the shape and internal organization of three PD families based on three different cores were probed by accurate, atomistic molecular dynamics simulations (MD). Particular care was taken to ensure complete structural equilibration by implementing an MD simulated annealing protocol prior to evaluation of the molecular structure and dynamics. All dendrimer families were found to be characterized by molecular dimensions in the nano-range, and by a shape-persistent, non-spherical structure, of molecular fractal dimension around 2.5–2.6, and of surface fractal dimension practically constant and almost equal to 2 with increasing generations in all cases. The MD analysis revealed also that, for this type of dendrimers, the starburst limited generation is presumably located in correspondence of the third generation.

Abdominal aortic aneurysm in patients affected by intermittent claudication: prevalence and clinical predictors

BackgroundAbdominal aortic aneurysm (AAA) is a frequent cause of death among elderly. Patients affected by lower extremity peripheral arterial disease (LE-PAD) seem to be particularly at high risk for AAA. We aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in a homogeneous cohort of LE-PAD patients affected by intermittent claudication.MethodsWe performed an abdominal ultrasound in 213 consecutive patients with documented LE-PAD (ankle/brachial index ≤0.90) attending our outpatient clinic for intermittent claudication. For each patient we registered cardiovascular risk factors and comorbidities, and measured neutrophil count.ResultsThe ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41 females, mean age 65.9 ± 9.8 yr) entered the study. Overall, AAA was present in 19 patients (9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p = 0.300). Patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015), were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count (5.5 [4.5 – 6.2] vs 4.1 [3.2 – 5.5] x103/μL, p = 0.010). Importantly, the c-statistic for neutrophil count (0.73, 95% CI 0.60 – 0.86, p =0.010) was higher than that for age (0.67, CI 0.56–0.78, p = 0.017). The prevalence of AAA in claudicant patients with a neutrophil count ≥ 5.1 x103/μL (cut-off identified at ROC analysis) was as high as 29.0%.ConclusionsPrevalence of AAA in claudicant patients is much higher than that reported in the general population. Ultrasound screening should be considered in these patients, especially in those with an elevated neutrophil count.

Computer-aided simulation of a dendrimer with a protoporphyrinic core as potential, novel hemoprotein mimic.

In this work, we have inserted the ion-heme group characterizing human blood in a class of synthetic, dendrimeric macromolecules, to evaluate a series of structural and physico-chemical properties related to the possible biological activity of these polymers. To this purpose, we have performed a complete series of investigations of five dendrimer generations both in vacuum and in water by molecular mechanics/dynamics simulations. To mimic oxygen binding, we have studied the same molecules in which the protoporphyrinic core was complexed to a Fe(II)-O(2)-hystidine residue. The main results of this study have led us to conclude that all dendrimer generations can bind oxygen stably, the fifth generation being the most affine to the myoglobin molecule, the natural carrier of blood oxygen.