Drug Discovery

Identifying new molecules of pharmacological interest is still one of the most critical steps in developing new therapies for patients with high unmet medical needs. Research typically begins with millions of chemical compounds with potential biological effects, only a handful of molecules are advanced to clinical testing. Advances in computing capacity and access to vast libraries of information via digital databases enable completely virtual initial screenings conducted "in silico"1 using software that conducts scientific experiments or research by means of computer modeling or computer simulation.

Dompé farmaceutici has seized the potential of bioinformatics by developing various platforms, such as Exscalate (EXaSCale smArt pLatform Against paThogEns), that leverage powerful supercomputers. This technological investment, consolidated over the years, has transformed our drug discovery process—making it more efficient to develop personalized therapies based on the characteristics of individual patients, especially in disease states that still face an unmet therapeutic needs.

Exscalate platform

Exscalate is a drug discovery platform boasting a library of compounds composed of 500 billion molecules, which can be evaluated at the rate of three million per second for each new target. In parallel to the library-based screening, we have developed an alternative drug repurposing process. The purpose of Exscalate is to identify molecules and compounds with structural characteristics capable of interacting with specific cell receptors to trigger specific biological activities. The software we use also allows us to design new molecules following the rules of rational drug design to obtain compounds capable of interacting specifically with a tissue or regulating the biological activity of a cell or a protein through specific receptors. Our supercomputing resources allow Exscalate to conduct simultaneous screening on several drugs, paving the way for a polypharmacological approach to the pathologies through multiple targets or disease pathways.

With the COVID-19 pandemic, Exscalate has driven the launch of Exscalate4CoV (E4C) project. This consortium, led by Dompé, includes 18 top public and private research institutions and centers, from seven different European countries, supported by the European Commission, under the Horizon 2020 framework program. E4C has used the platform to develop new drugs against Covid-192.

Hit-to-Lead (H2L)

Molecules selected in the HTS phase as having better in vitro activity than others are called hit compounds. Before being directed to clinical trials, these molecules undergo a further selection, which lasts approximately six to nine months, to verify that they are also selective molecules for the target of interest and that they have chemical-physical and pharmacokinetic characteristics suitable for the intended therapeutic purpose (for example, solubility). In this way, the most promising compounds, called lead compounds, are identified and sent to the next validation phase. The molecules that pass all the tests, indicated as lead candidates can finally be sent to the clinical phase 1 stage and beyond

Drug Discovery pipeline

Raloxifene hydrochloride

INN (International Non-proprietary Name): Raloxifene
phase II

Raloxifene hydrochloride is the hydrochloride salt form of raloxifene, a selective benzothiophene estrogen receptor modulator (SERM) with lipid-lowering effects and activity against osteoporosis. Raloxifene hydrochloride specifically binds to estrogen receptors in responsive tissue, including liver, bone, breast, and endometrium, and, after translocation to the nucleus, depending on the tissue type, it promotes or suppresses the transcription of estrogen-regulated genes, thereby exerting its agonistic or antagonistic effects. This agent functions as an estrogen agonist in lipid metabolism decreases bone resorption and bone turnover and increases bone mineral density. Raloxifene hydrochloride acts as an estrogen antagonist in uterine and breast tissue and exerts an anti-proliferative effect on estrogen-sensitive breast cancer.

Scientific literature reports the antiviral activity of raloxifene against Ebola virus, Hepatitis C virus, HBV, and Zika virus, and clinical efficacy as an adjuvant antiviral treatment of chronic hepatitis C, thus suggesting that the drug is a promising candidate for antiviral treatments.

Through the Exscalate supercomputing platform, and in the context of the funded EU grant EXSCALATE4COV (E4C) headed by Dompé Drug Discovery team, raloxifene was selected as a promising molecule to be studied as a possible treatment for mild to moderate COVID-19 patients due to its dual activity: 1) modulate SARS-CoV-2 viral replication and activity, and 2) interact with estrogen receptors that seem to play a key role in the protection against the virus via different mechanisms, confirming the hypothesis of raloxifene as a polypharmacological drug to fight SARS-CoV-2 infection.

On going Clinical studies

Trial to study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients

Drug Discovery publications

ACS Pharmacol. Transl. Sci. April 2022

Natural compounds inhibit SARS-CoV-2 nsp13 unwinding and ATPase enzyme activities

Angela Corona, Krzysztof Wycisk, Carmine Talarico, Candida Manelfi, Jessica Milia, Rolando Cannalire, Francesca Esposito, Philip Gribbon, Andrea Zaliani, Daniela Iaconis, Andrea R. Beccari, Vincenzo Summa, Marcin Nowotny, and Enzo Tramontano

PNAS April 2022

PKD-dependent PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 is required for E-cadherin transport from Golgi to plasma membrane

Giovanna Grimaldi, Angela Filograna, Laura Schembri, Matteo Lo Monte, Rosaria Di Martino, Marinella Pirozzi, Daniela Spano, Andrea R. Beccari, Seetharaman Parashuraman, Alberto Luini, Carmen Valente, and Daniela Corda

Frontiers in Pharmacology March 2022

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

Chiara Sfogliarini, Giovanna Pepe, Arianna Dolce, Sara Della Torre, Maria Candida Cesta, Marcello Allegretti, Massimo Locati and Elisabetta Vegeto

Frontiers in Pharmacology January 2022

The role of Interleukin-8 in lung inflammation and injury: implications for the management of COVID-19 and hyperinflammatory acute respiratory distress syndrome

Maria Candida Cesta, Mara Zippoli, Carolina Marsiglia, Elizabeth Marie Gavioli, Flavio Mantelli, Marcello Allegretti and Robert A. Balk.

Nucleic Acids Research November 2021

SCoV2-MD: a database for the dynamics of the SARS-CoV-2 proteome and variant impact predictions

Torrens-Fontanals, Talarico et al.

Cell Death & Differentiation August 2021

Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection

Marcello Allegretti, Maria Candida Cesta, Mara Zippoli, Andrea Beccari, Carmine Talarico, Flavio Mantelli, Enrico M. Bucci, Laura Scorzolini & Emanuele Nicastri

Journal of Cheminformatics volume 13 July 2021

“Molecular Anatomy”: a new multi-dimensional hierarchical scaffold analysis tool

Manelfi C et al.

American Journal of Transplantation May 2021

Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients

Piotr Witkowski, Martin Wijkstrom, Piotr J. Bachul, Katherine A. Morgan, Marlon Levy, Nicholas Onaca, Sushela S. Chaidarun, Timothy Gardner, A.M. James Shapiro, Andrew Posselt, Syed A. Ahmad, Luisa Daffonchio, Pier A. Ruffini, Melena D. Bellin

Int. J. Mol. Sci. May 2021

Altered Local Interactions and Long-Range Communications in UK Variant (B. 1.1. 7) Spike Glycoprotein

Stefano Borocci, Carmen Cerchia, Alessandro Grottesi, Nico Sanna, Ingrid Guarnetti Prandi, Nabil Abid, Andrea R. Beccari, Giovanni Chillemi and Carmine Talarico

Science May 2021

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Sebastian Günther et al.

Biomedicine and Pharmacotherapy April 2021

A new synthetic dual agonist of GPR120/GPR40 induces GLP-1 secretion and improves glucose homeostasis in mice

Gianluca Bianchini, Cecilia Nigro, Anna Sirico, Rubina Novelli, Immacolata Prevenzano, Claudia Miele, Francesco Beguino, Andrea Aramini

Biomedicines April 2021

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Cristina Giorgio, Mara Zippoli, Pasquale Cocchiaro, Vanessa Castelli, Giustino Varrassi, Andrea Aramini, Marcello Allegretti, Laura Brandolini and Maria Candida Cesta

ACS Pharmacol. Transl. Sci. March 2021

A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Jonas GossenJonas Gossen, Simone Albani, Anton Hanke, Benjamin P. Joseph, Cathrine Bergh, Maria Kuzikov, Elisa Costanzi, Candida Manelfi, Paola Storici, Philip Gribbon, Andrea R. Beccari, Carmine Talarico, Francesca Spyrakis, Erik Lindahl, Andrea Zaliani, Paolo Carloni, Rebecca C. Wade, Francesco Musiani, Daria B. Kokh, and Giulia Rossetti

ACS Pharmacol. Transl. Sci. March 2021

Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk JochmansDirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani

Molecules February 2021

Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

Candida Manelfi, Jonas Gossen, Silvia Gervasoni, Carmine Talarico, Simone Albani, Benjamin Joseph Philipp, Francesco Musiani, Giulio Vistoli, Giulia Rossetti, Andrea Rosario Beccari, Alessandro Pedretti

J. Med. Chem. November 2020

Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities

Cannalire R et al.,

International Journal of Molecular Sciences October 2020

Binding mode exploration of b1 receptor antagonists’ by the use of molecular dynamics and docking simulation—how different target engagement can determine different biological effects

Gemei M et al.

International Journal of Molecular Sciences August 2020

Sars-cov-2 entry inhibitors: Small molecules and peptides targeting virus or host cells

Cannalire R et al.

International Journal of Molecular Sciences July 2020

Computational studies of SARS-CoV-2 3clpro: Insights from md simulations

Grottesi A et al.

International Journal of Molecular Sciences July 2020

A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

Silvia Gervasoni, Giulio Vistoli, Carmine Talarico, Candida Manelfi, Andrea R. Beccari, Gabriel Studer, Gerardo Tauriello, Andrew Mark Waterhouse, Torsten Schwede and Alessandro Pedretti.

International Journal of Molecular Sciences April 2020

Combining Molecular Dynamics and Docking Simulations to Develop Targeted Protocols for Performing Optimized Virtual Screening Campaigns on The hTRPM8 Channel

C. Talarico et al.

Biomedicine & Pharmacotherapy March 2020

Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor

R D'Angelo et al.

European J of Medicinal Chemistry January 2020

Molecular modelling of epitopes recognized by neoplastic B lymphocytes in Chronic Lymphocytic Leukemia

Lupia A et al.

Neurotoxicity research July 2019

The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury

L Brandolini et al.

Cell March 2019

Auto-regulation of Secretory Flux by Sensing and Responding to the Folded Cargo Protein Load in the Endoplasmic Reticulum

Subramanian A et al.

Trends in Pharmacological Sciences June 2018

Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls

Allegretti M et al.

Bioinformatics March 2018

ADPredict: ADP-ribosylation site prediction based on physicochemical and structural descriptors

Lo Monte M et al.

Scientific reports September 2017

Novel Selective, Potent Naphthyl TRPM8 Antagonists Identified Through a Combined Ligand- And Structure-Based Virtual Screening Approach

AR Beccari et al.

The journal of physical chemistry October 2016

Conformational Change in the Mechanism of Inclusion of Ketoprofen in β-Cyclodextrin: NMR Spectroscopy, Ab Initio Calculations, Molecular Dynamics Simulations, and Photoreactivity

T Guzzo et al.

PNAS, Proceedings of the National Academy of Sciences PNAS, Proceedings of the National Academy of Sciences November 2014

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

Alessio Moriconi, Thiago M. Cunha, Guilherme R. Souza, Alexandre H. Lopes, Fernando Q. Cunha, Victor L. Carneiro, Larissa G. Pinto, Laura Brandolini, Andrea Aramini, Cinzia Bizzarri, Gianluca Bianchini, Andrea R. Beccari, Marco Fanton, Agostino Bruno, Gabriele Costantino, Riccardo Bertini, Emanuela Galliera, Massimo Locati, Sérgio H. Ferreira, Mauro M. Teixeira, and Marcello Allegretti

Journal of chemical information and modeling June 2013

LiGen: A High Performance Workflow for Chemistry Driven De Novo Design

AR Beccari et al.

Future Medicinal Chemistry May 2013

State-of-the-art and dissemination of computational tools for drug-design purposes: a survey among Italian academics and industrial institutions

Artese A et al.

Biochemical and Biophysical Research Communications October 2011

Exploring the activation mechanism of TRPM8 channel by targeted MD simulations

Pedretti A et al.

Journal of Medicinal Chemistry February 2010

Biological and Biophysical Properties of the Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Are Affected by the Presence of Short Alkyl Groups on the Phenyl Ring

Oger F et al.

Cell Press March 2008

Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls

Marcello Allegretti, Riccardo Bertini, Cinzia Bizzarri, Andrea Beccari, Alberto Mantovani and Massimo Locati

Current medicinal chemistry January 2005

Targeting C5a: Recent Advances in Drug Discovery

M Allegretti et al.

Journal of immunology November 1995

Mapping of Receptor Binding Sites on IL-1 Beta by Reconstruction of IL-1ra-like Domains

D Boraschi et al.

Drug Discovery stories


Trial to study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients

Brief summary

The objective of this study is to evaluate efficacy and safety of two doses of oral raloxifene in patients with early diagnosis of paucisymptomatic COVID-19. Efficacy will be assessed based on the proportion of patients with undetectable SARS-CoV-2 at day 7 after randomization and the proportion of patients who requires supplemental oxygen and/or mechanical ventilation by day 14 after randomization

detailed description

The Phase 2 of the trial was concluded at the end of June 2021 after enrollment and treatment of 70 patients. As of today, results are not yet publicly available.

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