BMS2052 Study Guide - Final Guide: Drug Design, Reverse Pharmacology, Antimicrobial Resistance
4 May 2018
School
Department
Course
Professor
Molecular Drug targets and Drug design
Early medicines were found from trial and
error in humans. Chinese medicine were
some of the earliest and most effective
Eg. Artemisinin (malaria drug). Early drugs
were restricted to plant extracts or
chemicals. Early antimicrobials included
quinine for malaria (from tree bark) and
mercury for syphilis. Systematic synthesis
of variants of trypan red gave rise to
compound 606 that could treat syphilis
start of modern drug discovery. Forward
pharmacology was used to discover
antibiotics.
Modern drug discover started with
systematic synthesis of chemical variants.
(systematically changing one part at a
time and testing it). Note that for
something to be a drug we don’t
necessarily have to know what it is or
what it looks like – it just needs to be
effective and safe.
Things that are systematically tested to be
potential drugs
- Small organic molecules (current
antibiotics are these)
- Proteinaceous are injectable
antimicrobial peptides and phage
lysins are proteins that can chew
through the bacterial cell wall.
- Nucleic acids (gene therapy
approaches) these are for longer
term problems
- Therapeutic vaccines combat
existing disease rather than
prevention – eg used in cancers
Antimicrobial resistance is for bacteria fungi
and parasites and is NOT limited to
antibiotics.
The drug pipeline takes 15years from pre-
discovery to market.
Academia period is the pre-discovery, drug
discovery and pre-clinical phases to find a
good target.
The Pharma phase covers pre-clinical
clinical trails 1 2 3 and approval market
phases.
Phase 1: small trial in healthy humans who DO
NOT HAVE disease needs to be safe
Phase 2: 500 people – target population to
see if the drug improves condition
Phase 3: global safety and efficacy –
compared against the gold standard
The pathway (look at diagram)
Academia reverse pharmacology finds the
drug target and characterises it Hit
candidate search (Hit is an active substance
that has desired antimicrobial action on
microbe or in a disease model do not need
to know what it is or how it works).
Pharma classical. Forward pharmacology
is screening for biological activity Hit
Once you have a Hit in vitro production
and re-test hit in a dose-response assay
aim to improve potence by making a
systematic change screening for activity
determining structural-activity relationship (if
activity is better keep it) can use C-ray
crystallography – speeds up process lead
optimisation (aim is to improve drug-like
properties whilst retaining potency)
Lead = candidate that pharmacological or
biological activity likely to be therapeutically
useful.
To find a drug target (identified in
fundamental research – reverse starts with
this to) a target inhibition or interference
with its activity will result in microbe death or
a reduction in virulence of the disease model.
Often a part of fundamental process required
for microbe survival. Can then do drug target
characterisation.
Document Summary
Early medicines were found from trial and error in humans. Chinese medicine were some of the earliest and most effective. Early drugs were restricted to plant extracts or chemicals. Early antimicrobials included quinine for malaria (from tree bark) and mercury for syphilis. Systematic synthesis of variants of trypan red gave rise to compound 606 that could treat syphilis start of modern drug discovery. Modern drug discover started with systematic synthesis of chemical variants. (systematically changing one part at a time and testing it). Note that for so(cid:373)ethi(cid:374)g to be a drug we do(cid:374)"t necessarily have to know what it is or what it looks like it just needs to be effective and safe. Things that are systematically tested to be potential drugs. Proteinaceous are injectable antimicrobial peptides and phage lysins are proteins that can chew through the bacterial cell wall. Nucleic acids (gene therapy approaches) these are for longer term problems.
