Search results for " Drug Discovery"

Reaction between Indazole and Pd-Bound Isocyanides-A Theoretical Mechanistic Study

2018

The mechanism of the addition of indazole (Ind)&mdash

Conformational response to ligand binding in phosphomannomutase2: insights into inborn glycosylation disorder.

2014

Background: Mutations in phosphomannomutase2 cause glycosylation disorder, a disease without a cure that will largely benefit from accurate ligand-bound models. Results: We obtained two models of phospomannomutase2 bound to glucose 1,6-bisphosphate and validated them with limited proteolysis. Conclusion: Ligand binding induces a large conformational transition in PMM2. Significance: We produce and validate closed-form models of PMM2 that represent a starting point for rational drug discovery.

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…

Monoclonal antibodies in gastrointestinal cancers

2013

Introduction: Among gastrointestinal cancers, colorectal and gastric neoplasms are the most frequent. The development of new targeted drugs improved the efficacy of systemic therapy in advanced stages of those malignancies. Areas covered: This review highlights the main biological processes implicated in gastrointestinal cancer development and progression, such as angiogenesis and epidermal growth factor receptor (EGFR) signaling pathway. On these bases, anti-EGFR and anti-vascular endothelial growth factor (VEGF) monoclonal antibodies in colorectal and gastric cancer are discussed. Data about further monoclonal antibodies in development are also reported. Expert opinion: The use of monoclo…

Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC)

2009

Background and aim: Translational data suggest that nucleoside transporters, in particular human equilibrative nucleoside transporter 1 (hENT1), play an important role in predicting clinical outcome after gemcitabine chemotherapy for several types of cancer. The aim of this study was to retrospectively determine patients' outcome according to the expression of hENT1 in tumoral cells of patients receiving gemcitabine-based therapy. Materials and Methods: The immunohistochemistry analysis was performed on samples from thirty-one patients with unresectable biliary tract cancer (BTC) consecutively treated with first line gemcitabine-based regimens. Results: Positive hENT1 staining patients were…

Prognostic and predictive biomarkers for targeted therapy in NSCLC: For whom the bell tolls?

2015

Introduction: The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical change in the treatment of several tumors, including NSCLC. In the last few years, the number of molecular biomarkers has rapidly increased, and a growing interest has been recently focused on their potential prognostic and predictive value in clinical settings. Areas covered: This review describes all the molecular biomarkers with prognostic and predictive value in NSCLC, including both clinically approved biomarkers, and emerging biomarkers under investigation in clinical trials. Liquid biopsy and applications of circulating biomarkers are also described. Expert opinion: The onco…

Synthesis and photocytotoxic activity of [1,2,3]triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines

2018

Abstract [1,2,3]Triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines were synthesized with the aim to investigate their photocytotoxic activity. Upon irradiation, oxazolo-naphtapyridines induced light-dependent cell death at nanomolar/low micromolar concentrations (EC50 0.01–6.59 μM). The most photocytotoxic derivative showed very high selectivity and photocytotoxicity indexes (SI = 72–86, PTI>5000), along with a triplet excited state with exceptionally long lifetime (18.0 μs) and high molar absorptivity (29781 ± 180 M−1cm−1 at λmax 315 nm). The light-induced production of ROS promptly induced an unquenchable apoptotic process selectively in tumor cells, with mitoch…

Monocyte to lymphocyte blood ratio in tuberculosis and HIV patients: Comparative analysis, preliminary data

2017

Recent data confirmed the hypothesis suggested by historical studies that the ratio of peripheral blood monocytes to lymphocytes (M/L) is associated with the risk of tuberculosis (TB) disease. We retrospectively analyzed the electronic health records of tuberculosis and HIV-positive patients who had followed day-care programs at the AIDS Center of the University of Palermo, Italy. 261 patients were recruited and divided into 6 groups as follows: healthy control group (HCG: 47 pts), latent HIV negative infected TB group (LIG, 43 pts), active HIV negative tuberculosis (TAG: 61 pts), treated tuberculosis HIV negative (TTG: 44 pts), HIV drug-naive patients tested TST and QFT-IT-negative with ne…

Osteoporosis risk factors in HIV positive women with osteoporosis: A retrospective analysis

2017

Multifactorial risk factors such as HIV/HCV co-infection and antiretroviral therapy (ARV) have been associated with osteoporosis in HIV+ women. We retrospectively analysed which known risk factors were associated with the diagnosis of osteoporosis, according to the WHO definition, in HIV positive women who were followed-up at the AIDS Centre of the University of Palermo, Italy between January 2011 and December 2014. Twenty-one HIV+ women with osteoporosis (13 HIV+ mono-infected and 8 HIV/HCV co-infected females) who underwent dual-energy X-ray absorptiometry (DXA) and liver stiffness assessment were included in the study. No significant differences between the HIV and HIV/HCV group were fou…

Aza-isoindolo and isoindolo-azaquinoxaline derivatives with antiproliferative activity

2015

Abstract Three new ring systems, pyrido[2′,3′:3,4]pyrrolo[1,2- a ]quinoxalines, pyrido[3′,2′:3,4]pyrrolo[1,2- a ]quinoxalines and pyrido[2′,3′:5,6]pyrazino[2,1- a ]isoindoles, were synthesized through an aza-substitution on the already active isoindolo-quinoxaline system and in particular in the position 7 or 4 of the isoindole moiety and in position 5 of the quinoxaline portion. All new compounds were screened by the National Cancer Institute (Bethesda, MD) against a panel of 60 human tumor cell lines. Biological results of the most active derivatives, with pGI 50 values between 7.09 and 7.27, confirmed the importance of the presence of methoxy substituents for biological activity. The ant…