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
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.
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
PNAS April 2022
PKD-dependent PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 is required for E-cadherin transport from Golgi to plasma membrane
Frontiers in Pharmacology March 2022
Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections
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
Nucleic Acids Research November 2021
SCoV2-MD: a database for the dynamics of the SARS-CoV-2 proteome and variant impact predictions
Cell Death & Differentiation August 2021
Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection
Journal of Cheminformatics volume 13 July 2021
“Molecular Anatomy”: a new multi-dimensional hierarchical scaffold analysis tool
American Journal of Transplantation May 2021
Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients
Int. J. Mol. Sci. May 2021
Altered Local Interactions and Long-Range Communications in UK Variant (B. 1.1. 7) Spike Glycoprotein
Science May 2021
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Biomedicine and Pharmacotherapy April 2021
A new synthetic dual agonist of GPR120/GPR40 induces GLP-1 secretion and improves glucose homeostasis in mice
Biomedicines April 2021
Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives
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
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
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
J. Med. Chem. November 2020
Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities
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
International Journal of Molecular Sciences August 2020
Sars-cov-2 entry inhibitors: Small molecules and peptides targeting virus or host cells
International Journal of Molecular Sciences July 2020
Computational studies of SARS-CoV-2 3clpro: Insights from md simulations
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
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
Biomedicine & Pharmacotherapy March 2020
Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor
European J of Medicinal Chemistry January 2020
Molecular modelling of epitopes recognized by neoplastic B lymphocytes in Chronic Lymphocytic Leukemia
Neurotoxicity research July 2019
The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury
Cell March 2019
Auto-regulation of Secretory Flux by Sensing and Responding to the Folded Cargo Protein Load in the Endoplasmic Reticulum
Trends in Pharmacological Sciences June 2018
Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls
Bioinformatics March 2018
ADPredict: ADP-ribosylation site prediction based on physicochemical and structural descriptors
Scientific reports September 2017
Novel Selective, Potent Naphthyl TRPM8 Antagonists Identified Through a Combined Ligand- And Structure-Based Virtual Screening Approach
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
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
Journal of chemical information and modeling June 2013
LiGen: A High Performance Workflow for Chemistry Driven De Novo Design
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
Biochemical and Biophysical Research Communications October 2011
Exploring the activation mechanism of TRPM8 channel by targeted MD simulations
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
Cell Press March 2008
Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls
Current medicinal chemistry January 2005
Targeting C5a: Recent Advances in Drug Discovery
Journal of immunology November 1995
Mapping of Receptor Binding Sites on IL-1 Beta by Reconstruction of IL-1ra-like Domains
Drug Discovery stories
RLX0120
Trial to study efficacy and safety of two doses of raloxifene in adult paucisymptomatic COVID-19 patients
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
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.
Click here to know more close