Notes 20100325 CS 683 Structural Bioinformatics Class
From SnOwy - Ed's Wiki Notebook
Contents |
Drug Discovery Continued
- iterative process
- narrow down the possibilities based on some hypotheses on the ligands for either positives or negatives
- creation of synthesized compound libraries
- bioinformatics allows virtual screening
- PubChem for instance has currently more than ten million compounds
- flat 2D projections are available from PubChem (some are available in 3D not all)
- the databases hold the user responsible for getting the 3D conformation
- gradient descent techniques used (on the 2D / 3D structure)
- iterative screening allows selection of yet better compounds per iteration
- software dealt with in virtual screening may not be ideal (i.e. true enough to life)
- relies on statistical analyses
- approximate
- all virtual screening is done with the idea that it's all an approximation
- ideal: deliverable in a pill, able to perform in mg concentrations per body mass
- must have a transient effect
- must operate on the desired binding site (side effects minimal)
- empirical evidence
- xray analyses coupled with affinity
- drug structure manipulated to increase potency
- often an iterative process
- synthesize and co-crystalize with protein
- drug design is multi-objective:
- attach to a candidate drug a long side chain that reduces its affinity for non-targets but not targets
- example: drugs that attack COX-1 COX-2 (cycloöxygenase)
- extra side chain has no particular benefit to target, just changes specificity
- scaffold -- rigid or flexible
- where scaffold is the stuff that does not immediately interact with binding sites (offers structural stability)
Drug Discovery Steps
- preclinical testing
- discovery steps takes 2 years
- watch the competition and create generic-brand drugs
- patent lifespan
- drug price plummets
- preclinical testing: lab and animal testing
- phase 1: healthy volunteers, safety and dosage determination
- phase 2: 100~300 patient volunteers, efficacy, side effects
- phase 3: (1~5)k patient volunteers, long term reactions
- FDA review and approval-- should look into process in Canada
- post-marketing testing
- total time cost 7~15 years
Notes
- start with compounds in order of 10k.
- patent procedure -- awareness that slight variations exist for drugs
- drug companies and patent offices make as broad a claim as possible
- early drug design: serendipity - making a discovery while looking for something else
- Amphetamine: originally a nasal decongestant
- LSD: originally for cardiovascular treatment
- Warfarin: low toxicity of rat poison in attempted suicide
- Viagra: antihypertensive
- leads must be optimized for activity, specificity and ADMET
ADMET
- Absorption
- Distribution
- Metabolism
- Elimination
- Toxicity
- Absorption deals with passage of drug into blood stream after ingestion
- first thing to survive is HCl in gut
- molecule must be small enough to fit through epithelium
- must be able to be transported in blood
- charged molecules have difficulty
- initially uncharged is good-- idea of prodrugs; liver (first pass effect), etc.
- pharmaceutical chemists may recognize a compound that would bind well but would never be absorbed
- distribution of the drug in body
- lipophilicity: drug accumulates in body's fatty tissues
- is drug free floating in blood or does it attach onto a plasma protein (transporter, carrier)
- prodrugs and stability
- prodrugs are compounds that are stable but pharmacologically inert
- converted by an enzyme to become the needed drug
- examples: P450 liver enzyme converts fluoxetine (Prozac) into norfluoxetine
- Seldane was a very popular antihistamine which had worldwide sales of over $1G.
- prodrug is a potent blocker of potassium channels: ventricular arrhythmias
- ketoconazole inhibits the conversion of terfenadine (Seldane-) to fexofenadine (Allegra-)
- implies that ketoconazole (anti-fungal agent) cannot be taken with Seldane
- syncope (dizziness), ventricular arrhythmia, cardiac arrest
- BRAIN AWAY™: If it's not there, it can't hurt you.
- Metabolism: biotransformation of the drug in other compounds (metabolites)
- more water soluble implies excretion from body via urinary system
- occurs mainly in liver also can occur in blood
- if drug is too rapidly metabolized, not enough left to have therapeutic effect
- lead poisoning, heavy metals are not eliminated and cannot be bound to some carrier to be excreted
- Elimination: degradative metabolites are removed; kidney, bowel, exhalation, sweating, breast milk
- elimination reduces bad side effects due to over dosing
- thalidomide example
- adequate clinical testing
- Toxicity: directly toxic or toxic metabolites
- metabolites are the most difficult to assess-- reminds me of a stochastic activity grammar
Drug Delivery
- oral (pill)
- inhalation (powder)
- parenteral (needle)
- rectal (suppository)
- transdermal (patch)
- bioavailability: oil versus water solubility
- prediction software used for bioavailability
- absorption: solubility, h-bonding, polar surface area, molecular weight, partition / distribution coefficient, pKa
- metabolism: liver, extrahepatic metabolism with bacteria in intestinal lumen
- hepatic portal system: hepatic clearance
- access of drugs to body tissues
- fat soluble or actively transported aqueous
- blood brain barrier
P-450 system
- CYP1A2: caffeine
- CYP2D6: fluoxetine
- CYP2E1: ethanol
- CYP3A4: cyclosporin, terfenadine, erythromycin, grapefruit juice (, a compound in)
Libinski's Rule of Five
- What properties make drugs different from other chemicals?
- World drug index (wdi)
- MW < 500 Daltons
- octanol/water partition coefficient < 5 (CLOGP)
- hydrogen bond doners < 5
- hydrogen bond acceptors < 10
