4thAdvanced

in silico Drug Design

KFC/ADD
Drug design intro
Karel Berka, Ph.D.
Pavel Polishchuk, Ph.D.
Thierry Langer, Ph.D.
Per Larsson, Thomas Evangelidis,
Václav Bazgier, Mariia Matveieva
UP Olomouc, 21.1.-25.1. 2019
 Motto
A pharmaceutical company utilizing computational
drug design is like an organic chemist utilizing an
NMR. It won’t solve all of your problems, but you
are much better off with it than without it.
DAVID C. YOUNG

Disclaimer:
Authors of this lecture series did not designed any drug in
common use.
Yet.
2
 Wednesday – towards the usage
Course Program • 9:30 De novo design (Polishchuk)
• 11:00 in silico drug delivery
Monday - basics
optimization (Larsson)
• 12:30 Drug design – intro (Berka)
• 12:00 lunch break
• 13:30 Virtual screening (Polishchuk)
• 13:00 Pharmacophores (Langer)
• 15:00 Chemical libraries (Polishchuk)
• 14:30 Tutorial–Pharmacophor(Langer)
• 16:00 Structural bioinfo tools (Berka)
• 18:00 Workshop diner
Thursday – structure-based methods
Tuesday – ligand-based methods
• 9:30 MM basics (Berka)
• 9:30 QSAR modelling (Polishchuk)
• 11:00 Molecular docking intro (Berka)
• 11:00 Deep learning (Evangelidis)
• 12:00 Lunch break
• 12:00 lunch break
• 13:00 Tutorial – Mol. docking (Berka)
• 13:00 Tutorial – Python, QSAR and
similarity search (Polishchuk, Matveieva)• 14:30 Tutorial – Mol. docking + MD
(Berka, Bazgier)
• 15:30 Tutorial – Deep learning
(Evangelidis) Friday – Challenge/hackathon
• 17:30 Excursion to IMTM (Polishchuk) • 9:00 Challenge (Polishchuk]
• 15:00 Final word (Berka) 3
 Ligand challenge
• Hackathon (Friday)
– Drug design for selected problem
– Selection of active compounds from the blind set
– Participation to hackathon is exam
requirement for Advanced Rational Drug
Design (4 ECTS credits)

4
 Literature
• Young, D.C. Computational Drug Design. Wiley, 2009.
• Young D.C. Computational Chemistry, a Practical Guide
for Applying Techniques to Real World Problems.
Wiley, 2001.
• Alvarez J. & Shoichet B. (Eds.). Virtual Screening in
Drug Discovery. Taylor&Francis, 2005.
• Berka K. & Bazgier V. Racionální návrh léčiv pomocí in
silico metod. UP Olomouc, 2015
(in Czech)
• Derek Lowe – In the pipeline blog
http://blogs.sciencemag.org/pipeline/
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SOURCES OF DRUGS
 History of Drug Design

1806

7
A. Cherkasov
 History of Drug Design
Time New Sources Testing Subjects

- ancient & plants, poisons (Paracelsus) humans

middle ages minerals ... natural sources
- 1806 morphine (first extracted) humans
- 1850 chemicals (chinin) humans (prisoners)
- 1890 synthetics, pigments animals
- 1920 animals, isolated organs
- 1970-1980 enzymes, cell lines (HeLa)
- 1990 High throughput libraries recombinant proteins
- 2000 chemical libraries chips, virtual screening,
ADMET testing

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 Sources of Drugs
All drugs by source, registered 01/1981 - 06/2006, FDA, n = 1184
S*; 4% V; 4%
N; 5% S; 30%
S*/NM;
10%
S/NM;
10%

B; 14% ND; 23%

B – biologicals, S/NM – synthetics mimicking natural
N – nature compounds, compounds,
ND – nature compounds derivatized, S* - synthetic, with pharmacophore
S – synthetic compounds, from natural compounds
D. J. Newman and G. M. Cragg, V - vaccines
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J. Nat. Prod. 70, 461-477 (2007)
 Idealized Drug Design Project
Illness
Identification of
lead compound
(2-5 let)

Isolation of
cause
(many years)

Preclinical Human clinical trials

testing on (2-10 years)
animals Formulation
(1-3 years) (1-3 years)

FDA approval
(2-3 years)
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Heal and Sell
 Vocabulary
• Target
– Biomolecule interacting with the drug
• Lead
– Base molecular structural motif of developed drug
• Hit
– Compound with positive hit in initial screening
• Candidate compounds
– Selected compounds used for next testing
• Efficacy
– Qualitative property – (drug heals or not)
• Activity
– Quantitative property – dosage needed for effect to happen
(pM – great, nM – excellent, μM – sufficient, mM – well…)
• Bioavailability
– Availability of compound in site of target in necessary concentration
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 Eroom’s Law

• Decline in pharmaceutical R&D efficiency –

halved per 9 years
– 'better than the Beatles' problem
– 'cautious regulator' problem
– 'throw money at it' tendency
– 'basic research–brute force' bias.
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Scannell JW, Blanckley A, Boldon H, Warrington B: Nature Reviews Drug Discovery 11, 191-200 (2012) doi:10.1038/nrd3681
 New Molecular Entities (NMEs)
FDA: EMA:
– approx. 30% - first in class – Rare diseases approx. 35%
– Rare diseases approx. 50% – Small molecules – approx. 70%
– Small molecules – approx. 80%

NMEs EMA
70

60

50 46
40 42
38 39
40 35
30
30 27

20

10

0
2011 2012 2013 2014 2015 2016 2017 2018

• https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/
• https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines/medicine-evaluation-figures
New FDA approved drugs from 2018
DRUG DESIGN
 Drug Design
Identification of new drug:
• Expensive problem
– Expenditures per 1 drug development - 2 600 000 000 USD1
+ expenses for production, patents, distribution…
 New drugs are expensive >1 000 USD/dose of drug2
• Hard problem
– Identification of target-drug pair is not simple
– ADMET
– Side-effects

1 - Tufts Center for the Study of Drug Development, 2014

2 – SÚKL, 3Q 2011, average price tag for most expensive drug category in CZ (over 10kCZK)
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 Expensive Problem
Experiment Cost per 1 compound

Virtual screening 100 CZK

Biochemical analysis 7 000 CZK
Cell culture testing 75 000 CZK
Acute toxicity on mice 250 000 CZK
Protein structure evaluation with X-Ray 2 000 000 CZK
Efficiency testing on animals 5 500 000 CZK
Chronic toxicity on rats 14 000 000 CZK
Clinical testing on volunteers 10 000 000 000 CZK

Lower price tag allow testing of more drug candidates

David C. Young - Computational Drug Design: A guide for computational and medicinal chemists.
Wiley-Blackwell, New York, 2009, ISBN 978-0470126851 17
 Hard Problem
• Human genom ~25 000 ORF
- Alternative splicing => ~500 000 proteins
~ 42 500 structures known human in PDB (11 200
unique)
- RNA role
- protein-protein interactions role

• 2 – 10 years from lead molecule identification to

clinical testing (patents last 20 years)

• 1 successful out of 10 drug development projects

www.rcsb.org - 20.1.2019 18
 Possible Obstacles
• Nonexistent testing model
– Example: HIV is human disease!
– Ethically not possible to test directly on people (cf. OS)
• Rare disease – orphan disease
– Future sales would not pay for regular development
– Orphan drug have lower requirements for registration
and individual incentives
• Too low activity of found drug
– Too toxic, bad bioavailability
• Active compounds are already patented
– Me2drugs
– Product has to be just as good as the one from
competition and patentable under our name
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 Illness Type
• Enzyme overproduction - some cancer types
– Inhibition (e.g. kinase inhibitors)
• High response of receptor – COX in pain
– Antagonists (e.g. pain relievers)
• Low response of receptor – neurological GPCRs
– Agonists (e.g. serotonin receptor agonists)
• Regulation peptide – CGRP peptide in migraine
– Antibodies (e.g. biologicals)
• RNA – RNAi, RNA aptamers…
– Emerging field
Small ligand with protein
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Most Typical Mechanism of Drug Action
• Lock and Key Analogon, 1894

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DRUG TARGETS
 Drug Targets

R. Santos, …, JP Overington: A comprehensive map of molecular drug targets. Nature Rev. Drug Discovery,
23
16, 19-34, 2017. doi: 10.1038/nrd.2016.230
 ATC code
• The Anatomical Therapeutic Chemical Classification System
code (ATC code) is attributed to a drug by the WHO
Collaborating Centre (WHOCC) for Drug Statistics Methodology.
– Level 1 – organ - (G): genito urinary system and sex hormones
– Level 2 – pharmacological action - (G04): urologicals
– Level 3 – pharmacological subgroup (G04B): urologicals
– Level4 – pharmacological subsubgroup (G04BE): in erectile dysfunction
– Level 5 - specific drug or combination (G04BE03): sildenafil
• a drug can have multiple codes,
– aspirin (B01AC06, A01AD05, N02BA01, N02BA51 and
N02BA71)

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 Drugs by ATC code

R. Santos, …, JP Overington: A comprehensive map of molecular drug targets. Nature Rev. Drug Discovery,
25
16, 19-34, 2017. doi: 10.1038/nrd.2016.230
 Drug Targets by ATC

R. Santos, …, JP Overington: A comprehensive map of molecular drug targets. Nature Rev. Drug Discovery,
26
16, 19-34, 2017. doi: 10.1038/nrd.2016.230
 Drug Target Types

> 60%
membrane
bound

Di Meo F, Fabre G, Berka K, Ossman T, Chantemargue B, Paloncýová M, Marquet P, Otyepka M, Trouillas P: In Silico
Pharmacology: Drug Membrane Partitioning and Crossing. Pharmacol. Res., 111, 471–486, 2016.
 Innovation Patterns in Privileged Classes
FURTHER INFORMATION
canSAR: https://cansar.icr.ac.uk
ChEMBL: https://www.ebi.ac.uk/chembl
Companion diagnostic test:
http://www.fda.gov/companiondiagnostics
Dronedarone prescribing information:
http://www.accessdata.fda.gov/drugsatfda_docs/
label/2013/022425s021lbl.pdf
DrugCentral: http://drugcentral.org
Illuminating the Druggable Genome:
https://pharos.nih.gov/idg/index
IUPHAR/BPS Guide to Pharmacology:
http://www.guidetopharmacology.org/GRAC
NCATS Pharmaceutical Collection:
https://tripod.nih.gov/npc/
ATC/DDD Index:
http://www.whocc.no/atc_ddd_index
WHO INN Drug lists: http://www.who.int/medicines/
publications/druginformation/innlists/en

R. Santos, …, JP Overington: A comprehensive map of molecular drug targets. Nature Rev. Drug Discovery,
28
16, 19-34, 2017. doi: 10.1038/nrd.2016.230
SMALL MOLECULES
Possibilities of in silico Drug Design
Known ligand Unknown ligand

Structure-based drug design De novo design

Known target

(SBDD)
structure

Docking

Ligand-based drug design CADD not possible

(LBDD)
Unknown target

some experimental
1 or more ligands data needed
• Similarity search
structure

Several ligands
• Pharmacophore ADMET filtering
Large number of ligands (20+)
• Quantitative Structure-Activity
Relationships (QSAR)
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BIOLOGICALS

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 Definition of Biological Product
• US:
– The term “biological product” or biologics means a
"any virus, therapeutic serum, toxin, antitoxin or
analogous product applicable to the prevention,
treatment or cure of diseases or injuries of man“
• EU:
– 'biological medicinal products' as "a protein or nucleic
acid–based pharmaceutical substance used for
therapeutic or in vivo diagnostic purposes, which is
produced by means other than direct extraction from a
native (nonengineered) biological source"
Ronald A Rader (Re)defining biopharmaceutical Nature Biotechnology 26, 743 - 751 (2008)
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doi:10.1038/nbt0708-743 32
 Small Molecules vz Biologicals
Chemical medicines are Biologics are grown from living things
chemicals made by Biologics are highly sensitive to
chemists out of other manufacturing conditions
chemicals

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 What are Biologicals?
• made of sugars, proteins, or nucleic acids or
complex combinations of these substances, or
may be living entities such as cells and tissues

• Like drugs, biological products are used to either:

– treat or cure diseases and medical conditions,
– prevent diseases, or
– diagnose diseases

• Biological products are made from a variety of

natural sources.
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 Types of Biological Products
• Blood Derivatives
• Whole Blood
• Blood Components
• Proteins
• Human Tissues
• Xenotransplantation Products
• Cellular & Gene Therapies
• Vaccines
• Allergenic Extracts

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 Size and Complexity of Biologicals in
Comparison with Small Molecules

Aspirin 180 Da

Monoclonal Antibody ~150,000 Da

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Protein Function Depend on Final
Configuration

37
Rational Protein Drug Design

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TAKE HOME MESSAGE
 Take Home Message
• Drugs comes from various sources
• Drug design is hard and expensive problem
– Mainly due to the biology and clinical trials costs!
• Most typical drug targets are:
– GPCRs, ion channels, nuclear receptors, kinases
– But - long tail of other drug targets – Orphans!
• Biologicals are more complex than small
molecules
• There is no gold path for drug design – the
methods have to be tied up to the current project