Search results for "positioning"
showing 10 items of 256 documents
Repurposing of Drugs Targeting YAP-TEAD Functions
2018
Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be rele…
Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells
2017
AbstractWe have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4. To identify proteins mediating apigenin’s effect, we next overlapped a 122-gene signature unique to HSCs with a list of 160 genes encoding…
Drugs Polypharmacology by in Silico Methods: New Opportunities in Drug Discovery
2016
Background Polypharmacology, defined as the modulation of multiple proteins rather than a single target to achieve a desired therapeutic effect, has been gaining increasing attention since 1990s, when industries had to withdraw several drugs due to their adverse effects, leading to permanent injuries or death, with multi-billiondollar legal damages. Therefore, if up to then the "one drug one target" paradigm had seen many researchers interest focused on the identification of selective drugs, with the strong expectation to avoid adverse drug reactions (ADRs), very recently new research strategies resulted more appealing even as attempts to overcome the decline in productivity of the drug dis…
Myotonic dystrophy type 1 drug development: A pipeline toward the market
2021
Highlights • Myotonic dystrophy, a neuromuscular disease, affects at least around half a million people worldwide. • Close to two dozen preclinical and clinical drug development programs active. • Drugs encompass new chemical entities, repurposing, oligonucleotide, and gene therapy. • Tideglusib, mexiletine, and metformin are close to reaching marketing authorization.
Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma
2021
A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein…
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
2018
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys–SOH) during crystallization. The P-glycoprotein efflux ratio was mea…
Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach
2018
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This netw…
A Deep Learning Model for Epigenomic Studies
2016
Epigenetics is the study of heritable changes in gene expression that does not involve changes to the underlying DNA sequence, i.e. a change in phenotype not involved by a change in genotype. At least three main factor seems responsible for epigenetic change including DNA methylation, histone modification and non-coding RNA, each one sharing having the same property to affect the dynamic of the chromatin structure by acting on Nucleosomes posi- tion. A nucleosome is a DNA-histone complex, where around 150 base pairs of double-stranded DNA is wrapped. The role of nucleosomes is to pack the DNA into the nucleus of the Eukaryote cells, to form the Chromatin. Nucleosome positioning plays an imp…
Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning.
2021
Coronavirus disease 2019 (COVID-19) is a major threat worldwide due to its fast spreading. As yet, there are no established drugs available. Speeding up drug discovery is urgently required. We applied a workflow of combined in silico methods (virtual drug screening, molecular docking and supervised machine learning algorithms) to identify novel drug candidates against COVID-19. We constructed chemical libraries consisting of FDA-approved drugs for drug repositioning and of natural compound datasets from literature mining and the ZINC database to select compounds interacting with SARS-CoV-2 target proteins (spike protein, nucleocapsid protein, and 2′-o-ribose methyltransferase). Supported by…
A webGIS-based system for real time shelf life prediction
2016
Technologies to acquire and monitor changes in the product shelf life were described.Four different SL predictive models were considered.A simulated transport using a prototype of Smart Logistic Unit was analysed.Real time shelf life prediction system was implemented in a webGIS platform. Shelf-life (SL) prediction and Least Shelf-life First Out (LSFO) stock strategy are important factors in perishable food supply chain in order to reduce quality and economic losses.In particular, distribution represents one of the main critical phases in logistic chain management and only the introduction of monitoring procedure can allow a reduction in food losses. Literature shows several mathematical mo…