Francesco Gentile

Francesco Gentile
Vancouver Prostate Centre | VPC · Department of Urologic Sciences

Doctor of Philosophy

About

41
Publications
7,804
Reads
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690
Citations
Introduction
I do research in the fields of anticancer and antiviral drug discovery, developing and applying physics-based and machine learning computational tools.
Additional affiliations
April 2019 - present
Vancouver Prostate Centre
Position
  • PostDoc Position
Education
September 2014 - January 2019
University of Alberta
Field of study
  • Biophysics
April 2012 - July 2014
Politecnico di Torino
Field of study
  • Biomedical Engineering
September 2008 - March 2012
Politecnico di Torino
Field of study
  • Biomedical Engineering

Publications

Publications (41)
Article
Full-text available
Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context,...
Article
Full-text available
Molecular docking is a well-established computational technique that aims to predict how a ligand binds to a specific protein target, as well as to assess the strength of the binding. Although docking programs are used worldwide for drug discovery, it is not always simple to identify which program or combination of programs provides the best result...
Article
Full-text available
The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5´‐3´ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherape...
Article
Full-text available
Drug discovery is a rigorous process that requires billion dollars of investments and decades of research to bring a molecule “from bench to a bedside”. While virtual docking can significantly accelerate the process of drug discovery, it ultimately lags the current rate of expansion of chemical databases that already exceed billions of molecular re...
Article
Full-text available
Recent explosive growth of 'make-on-demand' chemical libraries brought unprecedented opportunities but also significant challenges to the field of computer-aided drug discovery. To address this expansion of the accessible chemical universe, molecular docking needs to accurately rank billions of chemical structures, calling for the development of au...
Article
Full-text available
Inhibition of DNA repair enzymes is an attractive target for increasing the efficacy of DNA damaging chemotherapies. The ERCC1-XPF heterodimer is a key endonuclease in numerous single and double strand break repair processes, and inhibition of the heterodimerization has previously been shown to sensitize cancer cells to DNA damage. In this work, th...
Article
Full-text available
Deep learning has disrupted nearly every field of research, including those of direct importance to drug discovery, such as medicinal chemistry and pharmacology. This revolution has largely been attributed to the unprecedented advances in highly parallelizable graphics processing units (GPUs) and the development of GPU-enabled algorithms. In this R...
Article
With the recent explosion of chemical libraries beyond a billion molecules, more efficient virtual screening approaches are needed. The Deep Docking (DD) platform enables up to 100-fold acceleration of structure-based virtual screening by docking only a subset of a chemical library, iteratively synchronized with a ligand-based prediction of the rem...
Article
Deep learning (DL) can significantly accelerate virtual screening of ultra-large chemical libraries, enabling the evaluation of billions of compounds at a fraction of the computational cost and time required by conventional docking. Here we introduce DD-GUI, the graphical user interface for such DL approach we have previously developed, termed Deep...
Article
New disruptors of the ERCC1-XPF interaction interaction have a synergistic effect with traditional NER inhibitors, in p53 positive cells. Furthermore, the synergy can be resumed in p53 negative cells upon reactivation of the TP53 gene.
Article
Full-text available
The current COVID-19 pandemic has elicited extensive repurposing efforts (both small and large scale) to rapidly identify COVID-19 treatments among approved drugs. Herein, we provide a literature review of large-scale SARS-CoV-2 antiviral drug repurposing efforts and highlight a marked lack of consistent potency reporting. This variability indicate...
Article
Full-text available
PurposeThe ERCC1–XPF 5′–3′ DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to...
Article
Full-text available
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (M pro) responsible for cleavage at eleven positions along these polyproteins, including at its own N-and...
Article
The structure-specific ERCC1-XPF endonuclease is essential for repairing bulky DNA lesions and helix distortions induced by UV radiation, which forms cyclobutane pyrimidine dimers (CPDs), or chemicals that crosslink DNA strands such as cyclophosphamide and platinum-based chemotherapeutic agents. Inhibition of the ERCC1-XPF endonuclease activity has...
Article
Cover artwork: The cover image is based on the Research Article Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction by Francesco Gentile et al., https://doi.org/10.1111/cbdd.13660.
Article
Full-text available
The recently emerged 2019 Novel Coronavirus (SARS‐CoV‐2) and associated COVID‐19 disease cause serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vacci...
Preprint
div>The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no FDA-approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of nov...
Preprint
Full-text available
The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no FDA-approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel v...
Preprint
Full-text available
Drug discovery is an extensive and rigorous process that requires up to 2 billion dollars of investments and more than ten years of research and development to bring a molecule "from bench to a bedside". While virtual screening can significantly enhance drug discovery workflow, it ultimately lags the current rate of expansion of chemical databases...
Chapter
We have developed a novel, hybrid QSAR-docking approach (called ‘progressive docking’) that can speed up the process of virtual screening by enhancing it with Deep Learning models trained on-the-go on produced docking scores. The developed method can, therefore, predict docking outcome for yet unprocessed molecular entries and hence to progressivel...
Article
Full-text available
The ERCC1-XPF heterodimer is a 5´-3´ structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1-XPF is primarily involved in the repair of chemically-induced helix-distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand crosslinks. Inhibition of...
Chapter
Full-text available
The main objective of this review chapter is to give the reader a practical toolbox for applications in quantitative biology and computational drug discovery. The computational technique of molecular dynamics is discussed, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. Addi...
Article
Full-text available
The DNA excision repair protein ERCC-1-DNA repair endonuclease XPF (ERCC1-XPF) is a heterodimeric endonuclease essential for the nucleotide excision repair (NER) DNA repair pathway. Although its activity is required to maintain genome integrity in healthy cells, ERCC1-XPF can counteract the effect of DNA-damaging therapies such as platinum-based ch...
Article
Full-text available
The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate th...
Article
Full-text available
The mitotic kinesin Eg5 is an important target in cancer chemotherapy. A structurally diverse collection of canonical loop L5 inhibitors engage an allosteric pathway that includes elements of its microtubule binding region. However, recent evidence suggests that Eg5 may permit alternative allosteric mechanisms. Terpendole E, a natural-product Eg5 i...
Article
Full-text available
Background: A major class of chemotherapy drugs targets the genome of cancer cells. These DNA damaging agents induce damage to the DNA helix, resulting in the programmed death of cancer cells. An over-activated DNA repair mechanism in cancer cells can reduce the efficacy of these drugs, thereby eliminating their therapeutic benefit and developing...
Article
Full-text available
Toll-Like Receptors (TLR) are a large family of proteins involved in the immune system response. Both the activation and the inhibition of these receptors can have positive effects on several diseases, including viral pathologies and cancer, therefore prompting the development of new compounds. In order to provide new indications for the design of...
Article
Full-text available
A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas...

Projects

Projects (5)
Project
Development of methods and tools to improve structure-based virtual screening using machine learning.
Project
To discover small molecule inhibitors for key protein target of SARS-CoV-2 virus using an array of computer-aided drug discovery tools
Project
DockBox is a python wrapper library to facilitate the design, testing and application of new docking and scoring methods for drug discovery projects. Read-only free version of the original article is available at https://rdcu.be/bSQYt. The code is freely available at https://pypi.org/project/dockbox.