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.

ICM molecular files http://xablab.ucsd.edu/14/PROJ_CODE.icb Software: ICM-Browser

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, OCDTwo classes of neurons• Serotonergic neurons (5% of cells)• Glutaminergic neurons (80% of

brain cells) (e.g. Ketamine)

Targeting the 5-HT system• antidepressants, • antipsychotics, • anxiolytics, antimigraine• antiemetics,• psychedelic drugs

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

Drug: Fluoxetine/Prozac

20mg

Target Fluoxetine Norfluoxetine ADRSERT 1 19NET 660 2700DAT 4180 4205-HT2A 200 300CNS, hallucin./suicide5-HT2B ≥5000 ≥5100 heart valve disease5-HT2C 260 91Cortex, sleep/suicideM1 870 1200M2 2700 4600M3 1000 760M4 2900 2600M5 2700 2200

Polypharmacology, Kd (nM) and Adverse Effects

Norfluoxetine, fluoxetine's active metabolite made by Cytochrome P450

Fluoxetine

Becomes N+

Common adverse effects include:• Headache, Nausea• Insomnia AND drowsiness• Appetite loss. • Anxiety, Asthenia (weakness)• Diarrhea, Nervousness