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Summary Pre-clinical drug discovery
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Drug design and mechanisms of drug action - 1st semester Includes bullet points, key diagrams and images
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Preclinical Drug Discovery Target selection using SNPs (single nucleotide polymorphisms) and
GWAS (genome wide association studies) link SNPs to diseases
Target validation- In vivo evidence using animal models with disease,
knock out the gene but may be lethal, compensated or show any physical
symptoms
Target validation- In vitro evidence by creating tissue or cell models,
remove, over-express or under-express a gene. They avoid animals and
use simple organisms like yeast or cancer
High throughput screening (HTS)- tests compound with UV-vis,
fluorescence and radioactivity. Assays: enzyme (inhibitors/activators),
receptor assays (agonists/antagonists) and cell based
(pathways/genome)
Lead optimisations:
Identify SAR (structure activity relationships)- change in structure
changes activity
Identify pharmacophore- minimal feature essential for activity
Improve potency, selectivity, patent property and improve drug qualities
(metabolism, bioavailability and solubility)
Lipinski’s rule of 5- MW<500, H bond donors<5, H bond acceptors<10 and
log P<5
Log P- lipophilic compound are hydrophobic so insoluble or may bind too
strongly to plasma proteins. They tend to be metabolised faster so Log P
1.5-3 is typical
MW- increasing MW increases chance that sites get metabolised
H bond donors and acceptors- solvate in bulk water but must be
desolvated before absorbed through GI (requires energy). Donors have a
higher energy requirement than acceptors
Rotatable bonds<10 for bioavailability- flexibility allows binding to other
proteins (side effects) and rigidity locks it into the desired conformation
Total polar surface area<140A- high value means they’re too hydrophilic
Fraction of sp3 orbitals- number of sp3 carbons divided by total carbons
and Fsp3<0.4 is desired. Low value mean a flat compound with issues with
solubility and metabolism
Preclinical development- once optimisation phase is complete NCE (new
chemical entity) is developed
NCE- tests drug PK and PD in animal modes, 14 week safety study,
formulation studies and synthesis backup drugs
Toxicity- alkylating agents (halogens, epoxides, αβ unsaturated ketone
and quinones). Aromatic amines and thiocarbonyls can be metabolised to
toxic groups
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