Transcript Targeting the 5

PPharm Projects
Molecular Mechanism of Drug Action and Side Effects
• Form teams (A,B,…)
(check them online, under
‘News’)
• Install ICM-browser (link
online)
• Pick a disease-target
centered project
• Pick a subset of drugs for
the target
• Start collecting
information/images and
working on the
presentation
Sources of information
• Drugbank (drugs, properties, multiple targets)
• Wikipedia (disease, classes of drugs,
pharmacology)
• Protein Database Uniprot
• Protein Data Bank (PDB)
• Micromedex
• Early Drug Alerts (EDA):
ablab.ucsd.edu/~winston/
First steps
• From Disease to the Target
• Reduce your drug list to the interesting ones
with 3D, find files at the link below:
• Guidelines and Sample Templates Below.
Molecular 3D
ICM molecular files http://xablab.ucsd.edu/14/PROJ_CODE.icb
Software: ICMBrowser
The flow of slides
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Disease: basic facts, cost, number of patients..
Disease: molecular physiology and pathways
Disease targets: the main drug strategies/targets (the most recent drug target ideas)
Target: Your main drug target overview (domains, subtypes, localization, SNPs, mutation )
Drugs: Summary table (may take a few slides)
Drug1: (for each slide show the chemical structures and relevant parameters from
formulation to elimination), for example:
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Drug2:
Drug3:
..
Adverse effects and Polypharmacology (label, EDA/FAERS, final comparison table):
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Formulation & delivery (chemical structure of the crystal/salt)
Dissolution/ionization: logSw (and g/L)
Permeation and delivery to the target destination (CNS?), LogP/LogD, PSA
Activation to the physiological form (or forms) including ionization and chemical modification
(prodrug?)
Binding to the main target: pKd, DG, H Bonds, Shape, Hydrophobicity, 3D IMAGES
Half-life, elimination
Binding to other targets vs Adverse effects (see Drugbank, Wikipedia and Chembl)
Withdrawal or compliance/adherence effects
Future and needed improvements. Long term use prospects.
Sources and Acknowledgements
Depression, OCD and Serotonin
Transporters
Repetitive hand-washing is a
common OCD symptom
Van Gogh: Sorrowing old man
Disease: Depression, OCD
Two classes of neurons
• Serotonergic neurons (5% of cells)
• Glutaminergic neurons (80% of
brain cells) (e.g. Ketamine)
Serotonin and 5HT system
is produced, transported,
degraded, sensed
Targeting the 5-HT system
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antidepressants,
antipsychotics,
anxiolytics, antimigraine
antiemetics,
psychedelic drugs
Serotonin/5HT
MAO
Target: Serotonin Transporter (5HTT)
17q11.1–q12
• The serotonin transporter
removes serotonin from the
synaptic cleft back into the
synaptic boutons.
• It terminates the effects of
serotonin and simultaneously
enables its reuse by the
presynaptic neuron
• SNPs, personality traits and
Expression of Serotonin Transporter SERT: (solute carrier family 6
disease mutations are mapped member 4, neurotransmitter transporter)
on 5HTTLR
Gabrielsen M et al. LeuT-based
• (provide specific information to
model of SERT, JCIM, 2014
validate the connection with the
disease or comment on possible
drug resistance)
Drugs targeting 5HTT
• Provide information (in a table format) for each drug on
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Formulation, salt, racemic mix, activation/prodrug,
Physiological charge, pKa and site of absorption
LogP/LogD, Solubility, PSA
Dose (mg, mmol), Concentrations in moles/L
Additional instructions for the previous sample slide
Thermodynamics, kinetics, structural and molecular basis of:
– Dissolution/crystallization. Water solubility, for different crystal forms
where available.
– Ionization. Name ionizable groups with group-specific pKa where
available. Describe ionization forms prevalent at different pH. How does
ionization affect solubility? Recommendations for when to take it?
– Partition between aqueous and lipid phases. LogP value and
membrane permeation, PSA.
– Conformational transitions. Stereoisomers and their activity where
available. Chiral purity.
– Binding/dissociation reaction. Describe interactions with the target and
with other proteins, e.g. albumin and cytochromes where available
• Thermodynamics of binding (Kd if available, Ki or IC50), Free
concentrations/protein binding, relate to mg/kg
• Structural determinants of binding (shape, H-bonding), entropy
(compound flexibility analysis + hydrophobicity), allo/ortho-steric
nature of binding
Organize info in a table for several drugs
Becomes N+
Drug: Fluoxetine/Prozac
Fluoxetine
Norfluoxetine, fluoxetine's active
metabolite made by Cytochrome P450
Polypharmacology, Kd (nM) and Adverse Effects
Target
SERT
NET
DAT
5-HT2A
5-HT2B
5-HT2C
M1
M2
M3
M4
M5
Fluoxetine Norfluoxetine
1
660
4180
200
≥5000
260
870
2700
1000
2900
2700
19
2700
420
300
≥5100
91
1200
4600
760
2600
2200
ADR
CNS, hallucin./suicide
heart valve disease
Cortex, sleep/suicide
20mg
Common adverse effects include:
• Headache, Nausea
• Insomnia AND drowsiness
• Appetite loss.
• Anxiety, Asthenia (weakness)
• Diarrhea, Nervousness