2. Objectives
• Brief introduction to COVID-19
• Drug discovery process
• What is Drug Repurposing
• Strategies and Tools
• In silico Repurposing
• Repurposing of approved drugs
• A.I. for drug repurposing
• Future Perspective
3. Background
• Current global health distress: COVID-19
Pandemic
• COVID-19 is caused by severe acute respiratory
syndrome–coronavirus 2 (SARS-CoV-2)
• Currently, only supportive care is available.
• Research on the rapid development of new drug
molecules is highly risky and tedious process.
• Average cost of de novo drug development
reportedly over $1 billion USD
4. Origins of Human Corona viruses
• Severe acute respiratory syndrome coronavirus (SARS-CoV) - bats by
civet cats
• Middle East respiratory syndrome coronavirus (MERS-CoV) - dromedary
camels
• SARS-CoV-2 : likely pangolins https://www.mdpi.com/2076-0817/9/3/231/htm
5. Cellular uptake of the coronavirus
(A) Spike proteins on the surface of the coronavirus bind to
angiotensin-converting enzyme 2 (ACE-2) receptors on the
surface of the target cell;
(B) The type II transmembrane serine protease (TMPRSS2) binds to
and cleaves the ACE-2 receptor. In the process, the spike protein
is activated;
(C) Cleaved ACE-2 and activated spike protein facilitate viral entry.
TMPRSS2 expression increases cellular uptake of the coronavirus.
https://www.mdpi.com/2076-0817/9/3/231/htm
6. Coronavirus Replication in Host Cell
https://www.chemistryviews.org/details/ezine/11225161/Coronavirus_Entering_and_Replicating_in_a_Host_Cell.html
DOI: 10.1002/chemv.202000018
7. Cryo-electron microscopy (cryo-EM) structure of
the RNA-dependent RNA polymerase (RdRp)
RdRp is one of the main drug targets for SARS-CoV-2,
along with the virus’s spike protein.
RdRp is viral enzymes that replicate nucleic acids.
nsp=Non-structural protein (Science 2020 10.1126/science.abb7498).
8. ER: Endoplasmic reticulum
gRNA: genomic RNA
RdRp: RNA dependent RNA
polymerase
rhACE2: recombinant human
ACE2
sgRNA: subgenomic RNA
TMPRSS2: transmembrane
protease serine 2
R. Kiplin Guy et al. Science 2020;368:829-830
https://science.sciencemag.org/content/368/6493/829
Possible Targets in
Coronavirus Life cycle
9. Conventional Drug Development
• Although conventional drug development
aims to design drugs that selectively target a
single molecular entity (e.g., a disease-driving
protein), drugs often are found to interact
with more than one target.
10. Dug Discovery Process
Hampton, S.L., Kinnaird, A.I. Genetic interventions in mammalian cells; applications and uses in high-throughput screening and drug
discovery. Cell Biol Toxicol 26, 43–55 (2010)
11. Steps in early drug discovery
• Steps in early drug/probe discovery. Translational programs require stringent
target identification and validation information. Druggable targets are screened
either virtually using virtual compound structure databases or via biochemical or
cell-based assay screening of available chemical or peptide libraries. High
throughput Screening (HTS) can be performed with single purified compounds at
one or more concentrations (qHTS). Combination screens are performed to
identify synergistic combinations of bioactives. Drug repurposing screens identify
new targets for FDA-approved drugs, while multi-target drug discovery (MTDD)
approaches identify compounds with activity against two unrelated targets.
12. What is Drug Repurposing?
• Drug repurposing involves the developing of existing
drugs for new therapeutic purposes.
• The drug re-profiling, also coined the
term repurposing, repositioning, reusing and
rediscovery, is the usage of known drugs for new
diseases.
• Drug repositioning is often an indication expansion
with same mechanisms of action within same
therapeutic space. Eg. An anticancer drug repositioned
for another type of cancer
• Drug repurposing often involves extension into a new
therapeutic area, sometimes outside of the known
mechanisms of action and usually with a different
developer. Eg. Antimalarial drug to treat COVID-19
13. Drug Repurposing
• According to a BCC Research, “Global Markets for
Drug Repurposing,” the 30% repurposed drugs
account for 25% of the global pharmaceutical
industry revenues.
• Success rates for pre-approved drugs at 33% from
Phase I to market approval
• Investing in Orphan diseases - loss to pharma
companies – Hence, go for repurposing
• Repurposing is finding New indication.
• Serendipity : Phase III & IV
14. Drug Repurposing Historical Examples
Drug Name Existing Use Repurposing
Seldinafil Antihypertensive Erectile dysfunction activity
Aspirin NSAID Antiplatelet
Atorvastatin Lipid lowering Bone regeneration
Ketamine Anaethetic Pain and resistant depression
relief
Colchicine Gout Cardiovascular use
Artemisinins Antimalarial Anticancer
Minoxidyl Antihypertensive Hair growth
15. Drug Repurposing: Advantages
• Already in clinical use and known to be safe
• Shorter development time: Direct from Phase II
• Reduced costs
• Regulatory support
• Possible market exclusivity in the case
of drugs obtaining marketing authorization for
orphan conditions
• Higher probability of technical and commercial
success
16. Drug Repurposing: Regulatory advantage
• The FDA’s 505(b)(2) route and the Hybrid
Regulatory Pathway of the EMA are regulations
that allow the submission of previously generated
clinical data to support a repurposed product
approval.
• This includes in vitro and in vivo data, chemical
optimization, toxicology, CMC and formulation
development.
• 50% of NDA approvals from 2013-2018 were for
products submitted via the 505(b)(2) route
• Approval time: Repurposed drugs = 3 to 12 years;
de novo drugs = 10 to 17 years
17. Drug Repurposing: Disadvantages
• Dosing and Safety for new disease or indication
• Physicians need to be convinced of the additional clinical
value
• Difficult to convince stake holders about repurposing of
old failed drugs
• May precipitate adverse reactions. HCQ and AZ have
cardiac toxicity. HCQ on the eye.
• Complicated IP and exclusivity results in patent
infringement
• Hamper IP protection in case of published information
about the repurposed drugs
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285382/
18. Drug Repurposing Strategies:
How to work?
• Drug repurposing + Computational methods = “in
silico repurposing”
• Bioinformatics tools: in silico experiments such
as ligand-based and structure-based approaches
• Structure-based virtual screening and molecular
dynamics simulation which can find effective
compounds among existing drugs that may affect
on a specific molecular target.
• Advantage: Cheap and very fast screening
19. Structure-based drug discovery (SBDD)
• 3D structures of target proteins and small
molecule compounds studied by NMR, XRD.
• Used to determine how a small molecule (ligand)
affects structure and activity of protein
• Used for lead identification and optimization
which is partly based on virtual high-throughput
screening (VHTS)
• Methods: Molecular docking, Scoring and
molecular dynamics simulation
20. 6VXX Structure of the SARS-CoV-2 spike spike (S) glycoproteins promote
entry into cells and are the main target of antibodies
https://www.rcsb.org/structure/6VXX
21. • Using Structure-based virtual screening among
existing drugs that may affect on a specific
molecular target.
• Test the potential compounds in a realistic
environment, molecular dynamics simulation of
receptor and ligand conformations, to separate the
false positives and the true positives from each
other and finally identifying true “Hit” compounds.
• Technologies: 3D QSAR - Comparative molecular
field analysis (CoMFA) and comparative molecular
similarity indices analysis (CoMSIA), Docking
studies, MDS
• Identified potential compounds can be
straightaway taken to Phase 2 clinical trials.
Structure-based drug discovery (SBDD)
22. In Silico Repurposing
Molecular docking Computational determination of
binding affinity between Protein (target) and Ligand
(drug); to find best conformation; Rigid or flexible
docking.
Binding free energy of complex is determined.
• Tools: GOLD, SwissDoc, AutoDock Vina, Glide, Ledock
Scoring functions are mathematical methods used to
rank the ligands according to interaction energy
• Tools: DrugScore, X-Score, LigScore
Molecular dynamics simulation used to understand the
flexibility characteristics of biomolecules and how they
affect each other.
• Tools: Gromacs molecular dynamics package
23. Molecular Docking for Drug Repurposing
https://www.mdpi.com/1422-0067/20/18/4331/htm
24. QSAR
• Statistical approach: Relates physical and
Chemical properties of ligands to their
biological activities
• LogP, mol wt, no. of rotatable bonds are
critical
25. • A simplified flow chart of the procedures needed to perform an in silico
repurposing by using virtual screening and molecular dynamics simulation
methods
Quentin Vanhaelen (ed.),Computational Methods for Drug Repurposing, Methods in Molecular Biology, vol. 1903, Springer Nature 2019
QSAR & Machine
Learning
26. Repurposing of Drugs for COVID-19
• Existing Broad-spectrum antiviral agents (BSAAs) best
candidates Phases II though IV
• Umifenovir is a membrane fusion inhibitor targeting viral
entry
• Lopinavir/ritonavir is a drug combination - Influenza and
HIV - targeting viral protease
• Phase III level, Remdesivir, a viral RdRp (RNA-dependent
RNA polymerase) inhibitor, is under investigation
• Phase III level, Hydroxychloroquin/Chloroquine,
immunomodulator - antiviral activity at entry and post-
entry stages block autophagosome-lysosome fusion.
Synergistic with Remdesivir
27. Repurposing of Drugs for COVID-19
• Phase II clinical trial, Favipiravir is on a for novel
coronavirus-associated pneumonia
• Preclinical studies of Ribavirin (ribonucleic analog) has
shown in vitro activity against SARS-CoV-2
• Recombinant human ACE2 (rhACE2, or APN01) treatment
for acute lung injury and pulmonary arterial hypertension
• The TMPRSS2 inhibitor Camostat & nafamostat used for
chronic pancreatitis, block viral replication in TMPRSS2-
expressing human cells
• Azithromycin blocks autophagosome clearance in human
cells and Zika virus and influenza virus in human cells in
vitro Senanayake, S.L. Drug repurposing strategies for COVID-19.
Future Drug Discov., 2(2). 2020
29. Repurposed drugs under study
Drug Candidate MoA / indication Status/clinical trials Sponsor/Producer
Kaletra (lopinavir/ritonavir)
Combinational therapy
HIV protease inhibitor
HIV-1 infection
> 10 latest stages clinical studies
(Including combinations others)
AbbVie
Ganovo (Danoprevir) Hepatitis C virus protease inhibitor
Hepatitis C
Phase 4 Clinical Study
In combination with other drugs
Ascletis
The Ninth Hospital of Nanchang
Galidesivir (BCX4430) Nucleoside RNA polymerase
inhibitor Yellow Fever
Advanced development stage BioCryst Pharmaceuticals
BOLD-100 Inhibit stress-induced upregulation
of GRP78 Cancer drug
Suggested Bold Therapeutics
Leronlimab (PRO 140)
Humanized monoclonal antibody
Binds to CCR5
HIV, cancer
Initiation of Phase 2 Clinical Study CytoDyn Inc.
Ivermectin Anti-parasitic drug Preclinical study Doherty Institute
Monash University in Australia
Fingolimod Sphingosine 1-phosphate receptor
modulator Multiple sclerosis
Phase 2 Clinical Study in China First Affiliated Hospital of Fujian
Medical University
Thalidomide MoA is not fully understood Phase 2 Clinical Trials in China First Affiliated Hospital of Wenzhou
Medical University
Remdesivir (GS – 5734) Block RNA polymerase
Ebola
Orphan Drug Designation for Gilead
9 clinical studies worldwide
Gilead Sciences
Truvada (emtricitabine + tenofovir)
Combinational therapy
Non-nucleoside reverse
transcriptase inhibitors HIV
In preparation Gilead Sciences
Triazavirin inhibits RNA synthesis Phase 3 Clinical Study in China Health commission of Heilongjiang
province
Baricitinib JAK/NAK inhibitor
Rheumatic Disease
Phase 3 Clinical Study in Italy Hospital of Prato
Prezista/ Prezcobix (darunavir +
cobicistat) Combinational therapy
Protease inhibitor
HIV infection
Phase 3 Clinical Studies
in Spain 3C clinical Studies in China
Janssen Pharmaceuticals
Fundacio Lluita Contra la SIDA,
Medical Institutions in China
Chloroquine Endosomal acidification fusion
inhibitor Anti-malarial
> 10 studies worldwide
> 10 Clinical Studies in China
Medical institutions worldwide
30. Candidate MoA / indication Status/clinical trials Sponsor/Producer
Azithromycin Antibiotic > 10 trials in combination drugs Medical institutions worldwide
Remestemcel-L
Mesenchymal stromal cell (MSC)
Indication: Acute Graft versus Host
Disease
Phase III Clinical Trials Mesoblast, Inc. / Icahn School of
Medicine at Mount Sinai
Favipiravir (T-705) Block RNA polymerase
Flu drug
Approved in China Clinical studies
in China, Japan, and Italy
Produced by Fujifilm Toyama
Chemical
Kevzara (sarilumab)
Monoclonal antibody
Anti - IL-6
Rheumatoid arthritis
Phase 2, 3 Clinical Study Regeneron Pharmaceuticals,
Sanofi
EIDD-2801 Block RNA polymerase Suggested Ridgeback Biotherapeutics
Developed by Emory University
Activase Tissue plasminogen activator
Stroke drug
Suggested Roche (Genentech)
Actemra (tocilizumab)
Monoclonal antibody
anti-IL-6R
Rheumatoid arthritis
Approved in China 5 Clinical Studies
in Denmark, Italy, China
Roche,
Medical institutions worldwide
Umifenovir (Arbidol) Membrane fusion inhibitor Latest stages clinical studies in
China
(Including combinations with other
drugs)
Ruijin Hospital,
Other institutions in China
Ruxolitinib (Jakafi, Jakavi) Inhibitor of Janus-associated
kinases (JAK1 and JAK2)
Myelofibrosis
Clinical Study in China Ruxolitinib
combined with stem cell therapy
Tongji Hospital, Hubei, China
Tongji Hospital, Hubei, China
Manufacturer - Incyte Corporation
Camostat mesylate (Foypan) inhibit SARS-CoV-2 Spike protein-
initiated membrane fusion Post
refluxive esophagitis
Phase 1, 2 Clinical Study in
Germany
University of Aarhus
Manufactured in Japan
Nafamostat mesylate (Fusan) inhibit SARS-CoV-2 Spike protein-
initiated membrane fusion
Acute pancreatitis
Completed preclinical study in
Japan
University of Tokyo
Hydroxychloroquine
(Plaquenil)
Endosomal acidification fusion
inhibitor Anti-malarial Rheumatoid
arthritis treatment
> 10 Clinical Studies worldwide
10 Clinical Studies in China
Repurposed drugs under study
https://www.biopharmatrend.com/covid-19-treatments-and-vaccines/
31. Artificial Intelligence for Drug Repurposing
• Developing proprietary algorithms supporting AI
driven drug development
• Predicting the 3D Structure of a Target Protein;
Drug–Protein Interactions
• Traditional high-throughput screening (1 one
million compounds), where each compound
typically costs 50–100 USD total several million
USD & several years to identify lead compound.
• By contrast, with the help of AI, a virtual
compound library of several billion molecules can
be screened within a few days. Less than 1 year
lead compound
https://pubmed.ncbi.nlm.nih.gov/31651216/
https://www.alacrita.com/blog/the-risk-reward-balance-in-drug-repurposing
32. AI based Drug Repurposing by Companies
• Known as deepDTnet, this methodology embeds
a network connecting drugs, targets and diseases
and, via deep learning, infers the targets with
which a drug will interact
• UK-based Healx – gene mapping and repurposing
in the rare diseases
• SOM Biotech and Pharnext in CNS indications
• Algernon - inflammation and fibrosis
• Big Pharma and Novartis and ofatumumab
(Arzerra), a CD20 monoclonal antibody used
earlier for for leukemia
• GVK BIO provides CRO service on AI
https://pubmed.ncbi.nlm.nih.gov/31651216/
https://www.alacrita.com/blog/the-risk-reward-balance-in-drug-repurposing
33. COVID-19 Drug Repurposing Database
• COVID-19 Drug Repurposing Database
• Excelra’s open-access database
• ‘Approved’ small molecules and biologics, which can rapidly
enter either Phase 2 or 3, or may even be used directly in
clinical settings against COVID-19.
• Clinical, pre-clinical and experimental stages of drug
discovery and development.
• https://www.excelra.com/covid-19-drug-repurposing-
database/
34. Future perspective
• Due to lack of specificity of BSAAs may result in the
emergence of drug resistance and more virulent strains
• Drug repurposing will have to compete with structure-
based design of small molecules on efficacy and off-
target toxicity studies. The CoV spike glycoprotein used
by SARS-CoV-2 at the atomic resolution and human
ACE2 enzyme as its port of cellular entry have now
been determined
• Machine learning approaches can be implemented to
support and expedite drug discovery
• Patent protection: Drug Regulators should liberalize
drug licensure through repurposing if necessary