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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) Pick a disease-target centered project Pick a subset of drugs for the target
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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. Molecular 3D
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, 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 • 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 disease mutations are mapped on 5HTTLR • (provide specific information to validate the connection with the disease or comment on possible drug resistance) Expression of Serotonin Transporter SERT: (solute carrier family 6 member 4, neurotransmitter transporter) GabrielsenM 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 (Kdif 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
Drug: Fluoxetine/Prozac Becomes N+ Fluoxetine Norfluoxetine, fluoxetine's active metabolite made by Cytochrome P450 20mg Polypharmacology, Kd (nM) and Adverse Effects TargetFluoxetineNorfluoxetine ADR SERT 1 19 NET 660 2700 DAT 4180 420 5-HT2A 200 300 CNS, hallucin./suicide 5-HT2B ≥5000 ≥5100 heart valve disease 5-HT2C 260 91Cortex, sleep/suicide M1 870 1200 M2 2700 4600 M3 1000 760 M4 2900 2600 M5 2700 2200 • Common adverse effects include: • Headache, Nausea • Insomnia AND drowsiness • Appetite loss. • Anxiety, Asthenia (weakness) • Diarrhea, Nervousness