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Chapter 2 Drug screening & discovery (design)口服药物的共性:
Small is better (sample bigger chemical space, higher hit rate, higher Ligand Efficiency, less false positive results, more intuitive to medicinal chemists)
7 、 Fragment based lead discovery
Fragment Library
Target
X-ray / NMR Structures
b ca
NMR CompetitiveBinding Experiment
ON
NH
N
O
O
NH
N
NH
O
OH
O
NHN
NNH
NH
ONH
N
NH
NNH
OH
O
N
NH
NNH
NH
N
NH
O
O
NH2
O
NH
NH
Evolution
Validation Biacore
HSQC
*Hubbard et al (2007), Curr Topics Med Chem, 7, 1568
Biacore
Fragment Based Lead Discovery
Clinical candidates of fragment-derived compounds
Compound Company Status Target Therapy areas
Vemurafenib Plexxikon/Roche
Phase IV B-RAF Melonoma (first FBDD drug on market, FDA approved in 2011)
ABT-263 Abbott Genentech
Phase II Bcl-xL Small-cell lung cancer, CML, Lymphoma, Hematological neoplasm Cancer
ABT-869 Abbott Phase II VEGF and PDGF receptor tyrosine kinase family members
Non-small-cell lungcancer, etc.
AT-7519 Astex Phase II CDK family members
Multiple myeloma cancer
AT-9283 Astex Phase II Aurora kinase family members
Flt3 tyrosine kinase, Jak2 tyrosine kinase
Abl tyrosine kinase
Hematological
neoplasm
Solid tumor
Compound Company Status Target Therapy areas
DG-051 deCODE Phase II Leukotriene A4
hydrolase
Myocardial infarction
PLX-204 Plexxikon Phase II PPAR alpha, delta, gamma
Inflammatory disease
Cardiovascular disease
Non-insulin dependent
diabetes
LY-517717 Lilly Tularik Phase II Factor Xa Thrombosis
Phase I Raf protein kinase Pain, Polycystic kidney disease
SNS-314 Sunesis Phase I Aurora protein kinase
Cancer solid tumor
AT-13148 Astex, ICR CRT AstraZeneca
Phase I AKT protein kinase
Cancer
SGX-393 Lilly (SGX) IND for Phase I
Abl tyrosine kinase
Cancer
Ref: Expert Opin. Drug Discov. (2009) 4:1125
Weak binding between the target and a small molecule fragment is detected by biophysical methods, e.g., NMR, SPR or cross-validated by these two techniques.
Fragment Selection
RO3:
110 < MW <250 ~ 300
cLogP < 2 ~ 3 (or cLogD < 2 ~ 3)
2 < N+O < 6
logS > -4.5
TPSA < 110
Maximize the shape and electrical diversities (Openbabel + Pipeline Pilot) to cover the chemical space for prototypical compounds
High ligand efficiency
LE = RTln(KD)/HAC
LE improves from ~0.3 to ~0.5 during hits to leads (H2L)
Final:
1K~2K fragment library (Commercial library: Maybridge or Chembridge)
Most used Fragments Screening methodsScreening
methodLibrary
sizePrimary
screeningProtein amount
Pros & Cons
Crystallography
1K N >10mg • Low hit rate, low throughput• Heavily involved in H2L, LO.
NMR 1K Y >10mg • High hit rate (2~8%, indicate druggability).• Ligand based (STD & WaterLOGSY) observation in cocktail•Less false positive results
ITC 1 – 2K N ~g
SPR 2 – 5K Y ~mg • 3 weeks screening• Cross validation with NMR
HCS 5 – 30K Y • require bioassay development for different targets (difficulty in outsourcing) • High false positive rate
>10 fragment derived compounds in clinical phase II from pharmaceutical companies, e.g., Novartis, Lily, Abbott, Genentech, Astex, Vernalis, deCODE, Plexxikon.>20 fragment derived compounds in clinical phase I since 2005.