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
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PPharm Projects Molecular Mechanism of Drug Action and Side Effects Form teams (A,B,…) (check them online, under ‘News’) Install ICM-browser (link online)
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PPharm ProjectsMolecular 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.
The flow of slides• 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: – 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)
• Drug2:• Drug3: • ..• Adverse effects and Polypharmacology (label, EDA/FAERS, final comparison table):
– 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, OCDTwo classes of neurons• Serotonergic neurons (5% of cells)• Glutaminergic neurons (80% of
Serotonin and 5HT systemis produced, transported, degraded, sensed
MAO
Serotonin/5HT
Target: Serotonin Transporter (5HTT)
Expression of Serotonin Transporter SERT: (solute carrier family 6 member 4, neurotransmitter transporter)
• 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 disease mutations are mapped on 5HTTLR
• (provide specific information to validate the connection with the disease or comment on possible drug resistance)
17q11.1–q12
Gabrielsen M et al. LeuT-based model of SERT, JCIM, 2014
Drugs targeting 5HTT
• Provide information (in a table format) for each drug on– Formulation, salt, racemic mix, activation/prodrug, – Physiological charge, pKa and site of absorption– LogP/LogD, Solubility, PSA– Dose (mg, mmol), Concentrations in moles/L
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
Additional instructions for the previous sample slide