The Drug Research Phase:

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The Drug Research Phase
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From Hits to Leads
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The Lead Discovery Process
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The "Hit-to-Lead" Process
Questions to ask the "candidate" (Hit) - Is hit
selective with respect to other HTS assays? - How
many similar compounds can be found ...in the
hitlist of this assay (active analogues)? ...in
the whole company pool (active and inactive
analogues)? - Can we detect SAR/pattern of
activity ...in the HTS data? ...in the IC50
data? ...in both? - Which hits are "druglike"?
(Pharmacokinetics) - What about physicochemical
(PC) properties of the hits?
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The HTS Data Analysis Workflow

• Check activity distribution profiles and
  statistics gt hit definition and identification

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SPA ? Principle
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The HTS Data Analysis Workflow

• HTS typically runs at single compound
  concentrations (e.g. 10-5 molar)
• Activity data are expressed relative to negative
  controls (buffer)
• 100 of control inactive (as negative control)
• lt100 of control inhibition of target
• gt100 of control stimulation of target

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Activity Distribution Profile
Mean 100 Ctrl Standard Deviation 12
Mean 97 Ctrl Standard Deviation 25
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Activity Distribution Profile
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The HTS Data Analysis Workflow

• Check activity distribution profiles and
  statistics
• Check selectivity with respect to other HTS
  assays

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Selectivity Profile
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The HTS Data Analysis Workflow

• Check activity distribution profiles and
  statistics
• Check selectivity with respect to other HTS
  assays
• Cluster hitlist by similarity

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Clustering of Hits within Hitlist
Hit Clusters
Chemical Space of Hitlist
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The HTS Data Analysis Workflow

• Check activity distribution profiles and
  statistics
• Check selectivity with respect to other HTS
  assays
• Cluster hitlist by similarity
• For each hit, search for similar compounds in
  whole company pool (-gt "nearest-neighbor
  list")

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Searching for "Nearest-Neighbors" in whole
company pool
HTS Hit
Nearest Neighbors
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The HTS Data Analysis Workflow

• Check activity distribution profiles and
  statistics
• Check selectivity with respect to other HTS
  assays
• Cluster hitlist by similarity
• For each hit, search for similar compounds in
  whole company pool (-gt "nearest-neighbor
  list")
• Within each nearest-neighbor list, try to find
  structure-activity relationships (SAR)

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Fragment-based SAR elucidation
Structure-Activity Relationships
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Fragment-based SAR elucidation
Positive effect on activity
Negative effect on activity
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Lead Optimization - From Leads to Developmental
Candidates -
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(No Transcript)
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What do we want to optimize??
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• Lead Optimization Issues in Medicinal Chemistry

• Pharmacodynamics
• Potency (binding affinity), Efficacy
• Pharmacokinetics
• ADME (Absorption, Distribution, Metabolism,
  Elimination)
• Toxicology
• Physicochemical (PC) properties
• Solubility, crystal modification etc.

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Pharmacodynamics How the drug impacts the
body Pharmacokinetics How the body impacts the
drug
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Routes of Administration

• A drug can be applied in different ways
• oral (per os, p.o.)
• intravenous (i.v.)
• subcutaneous (s.c.)
• intramuscular (i.m.)
• sublingual
• inhalative
• dermal, transdermal
• intranasal
• rectal, intravaginal

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ADME - The faith of the drug in the body

• Absorption
• most drugs have to cross membranes
• exception topical administration (e.g. dermal)
• Distribution
• the drug has to reach its desired point of action
  (e.g. brain, lung, heart, liver etc.)
• Metabolism
• most drugs are modified by the body
• Elimination
• drugs should not accumulate in the body

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Absorption The gastrointestinal (GI-)Tract
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Absorption Most drugs have to cross membranes

• Drugs can cross membranes via
• passive diffusion
• active transport

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Absorption Molecular Structure of the
phospholipid membrane
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Absorption Passive Diffusion
D kP
Fick's Law
P distribution coefficient (octanol/water)
q diffusion rate A membrane area d membrane
thickness (Co-Ci) concentration gradient D
diffusion coefficient
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Absorption Active Transport by Carrier Proteins
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Oral drug absorption Is it possible to predict
from molecular structure?
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Lipinski's Rules of Fiveas a filter for oral
drug absorption
Accumulated property distribution of about 2200
Phase II compounds
(Lipinski et al., Adv. Drug Deliv. Rev. 1997, 23,
3-25)
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Lipinski's Rules of Fiveas a filter for oral
drug absorption

• Poor absorption or permeation are more likely
  when there are
• More than 5 H-bond donors (NH's OH's)
• The Molecular Weight is over 500
• The logP is over 5
• The sum of N's and O's is over 10
• Substrates for transporters and natural products
  are exceptions

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Polar Surface Area (PSA) as a filter for oral
drug absorption
Oseltamivir
Zanamivir
Polar Surface Area Unpolar Surface Area
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Polar Surface Area (PSA) as a filter for oral
drug absorption
Rule of thumb The PSA should not exceed 140 Å2
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Oral drug absorption
Top-selling drugs obey Lipinski and PSA rules
of thumb!
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Oral drug absorption
- Poor intestinal absorption - Must be
applied as inhalent
- Orally active - Applied as capsules
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Oral drug absorption
Binding of Zanamivir and Oseltamivir to
Neuraminidase