Download - Mc06 2009
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Dr. Antonio DelgadoProfesor Titular de la Universidad de BarcelonaFacultad de FarmaciaUnidad de Química Farmacéutica (Unidad Asociada al CSIC) (Abril-Mayo 2009)
UNIVERSITAT DE BARCELONA
MC06: Hit to Lead Optimization
Medicinal Chemistry & Molecular DesignPrograma de doctorado: “Mechmod”
Universitat de Girona
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Hit: Substance that produces a significant response in a screen (usually isolated enzymes or cell extracts) designed to reveal promising substances.
Lead: A molecular modification of a hit that produces promising activity in a whole cell, intact organ system or whole animal, confirming the relevance of the activity found in the initial screen.
Candidate drug: A lead that shows promising properties in more than one relevant animal species suffering from a model disease.
Clinical candidate: Selected molecule for further development and biological evaluation in humans.
Drug: Molecule that has passed successfully through all the above stages and advances into human use.
Some basic concepts
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A suitable lead substance
Other properties that must be considered in a drug
Toxicity (acute, chronic)MutagenicityStabilityFormulabilityPatentabilityCost
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Diseño racional
Azar
Origen Posibles ventajas Posibles limitaciones
Productos naturales Singularidad Solubles en agua
Estructura compleja Pequeñas cantidades
Cribado de colecciones elegidas al azar (HTS)
Diversidad Costosas Posibilidad de compuestos con propiedades físicas inadecuadas (PM, clogP)
Fármacos conocidos Propiedades adecuadas Pocas modificaciones estructurales
Limitaciones derivadas de la propiedad intelectual (patentes)
Ligando endógeno Racional Colecciones dirigidas
Conocimiento del ligando Conocimiento del proceso bioquímico
Diana terapéutica Racional Diversidad Nuevas cabezas de serie
Conocimiento de la diana terapéutica Posibilidad de compuestos con propiedades físicas inadecuadas (PM, clogP)
Posibilidades para el descubrimiento de nuevos fármacos
Origen de hits
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Active compounds of natural origin• Plants
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CH3O
CH3O
CH3O
NH
O
CH3O
C CH3
O
HN
HN
OO
O–
CH2OH
HH
HOH2N
HO
H
OHHO
O
HOH
O
NCH3
OCH3
NH
O
CH3
CH3
tetrodotoxina
batracotoxina
+
• Animals
colchicina
Active compounds of natural origin• Plants
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N
S CH3
CH3
O
H
COOH
HHNC
O
R
Active compounds of natural origin• microorganisms
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Diseño a partir de productos naturales
Farmacomodulación disyuntiva
CH3H
O
H3C
O
H3C
CH3
O
OHO
C6H5
CH3
H3C
O
OHO
F
HMGCoA-reductase inhibitors
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Farmacomodulación disyuntiva(Apertura de anillos)
NH3C CH3
CH3
OHlevorfanolmetazocina
N
CH3
CO2C2H5
petidina
H3CN
CH3COC2H5
CH3
metadona
NH3C
OH
NH3C
OH
OHO
morfina
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Semisíntesis (síntesis parcial)
N
S CH3
CH3
O
H
COOH
HHN
bencilpenicilina(penicilina G)
O
penicilín acilasa
N
S CH3
CH3
O
H
COOH
HH2N
6-APA
COOH
ácido fenilacético
N
S
O
H2N
RCOOH/DCC*
O
CR Cl
O
CR N3
O
CR
O
CRO
base
base
N
S
O
HN
O
R
*DCC: N,N'-diciclohexilcarbodiimidaN C N
Et3N
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Semisíntesis (síntesis parcial)
Extracción a partir de las hojas de Taxus bacata (aprox 1g/Kg)
TaxolAnálogos estructurales
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From hit to lead: the problem of target identification
Bioactive compounds
Targets
Rational d
esign
Forward chemical genetics(Ligand-based approach)
Reverse chemical genetics(Receptor-based approach)
GenomicsStructural knowledge
(X-ray, NMR)
Hits(natural products, HTS,
ligands)
Target identificationLigand identification
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Genética química
(“chemical genetics”)
Empleo de moléculas para obtener información alternativa y/o complementaria a la que se obtiene mediante métodos basados en la genética clásica
Y.-H. Ahn and Y.-T. Chang, Tagged Small Molecule Library Approach for Facilitated Chemical Genetics. Acc. Chem. Res. 2007, 40, 1025-1033.
D. P. Walsh and Y. T. Chang, Chemical Genetics. Chem. Rev. 2006, 106, 2476-2530.
D. R. Spring, Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev 2005, 34, 472-482.
S. M. Khersonsky and Y. T. Chang, Strategies for facilitated forward chemical genetics. Chembiochem 2004, 5, 903-908.
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“Forward chemical genetics”
Síntesis de nuevas moléculas y cribado orientado a la evaluación de una función celular
“Forward genetics”
Experimentos basados en la genética clásica por los que se identifican nuevos
componentes (enzimas o receptores) de un proceso celular particular
Descubrimiento de nuevas dianas celulares (proteínas)
¿Dónde actúan los compuestos?
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“Forward genetics”
1. Generación de mutantes
2. Cribado para identificar alteraciones en el fenotipo (variación funcional del proceso celular de interés)
3. Identificación de las mutaciones en los genes específicos que dan lugar al fenotipo observado
4. Identificación de la proteína codificada (diana molecular) por el gen objeto de la mutación
Zebrafish (Danio rerio)adult (up) and larvae (left)
Mutated larvae
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“Forward chemical genetics”
1. Generación de colecciones combinatorias (“diversity oriented synthesis “DOS”)
2. Cribado (HTS) para identificar alteraciones en el fenotipo (variación funcional del proceso celular de interés)
3. Identificación de las moléculas activas (inhibición de un proceso celular)
4. Identificación de la diana molecular (proteína inhibida)
Use target compound to pull out protein responsible for phenotype and identify gene that codes for the protein
¿Dónde actúan los compuestos?
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El problema de la identificación de la diana
Ahn, Y.-H.; Chang, Y.-T., Tagged Small Molecule Library Approach for Facilitated Chemical Genetics. Acc. Chem. Res. 2007, 40, 1025-1033.
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El problema de la identificación de la dianaTraditional Approach
MS microsequencing
Spring, D. R., Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev 2005, 34, 472-482.
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“Reverse chemical genetics”
Identificación de ligandos específicos para una proteína determinada.
“Reverse genetics”
Experimentos basados en la genética clásica por los que se pone de manifiesto la función
de una proteína determinada
Información sobre la función de una proteína particular
¿Cuáles son los ligandos una proteína?
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“Reverse genetics”
1. Mutaciones dirigidas a la proteína diana
2. Cribado dirigido al estudio del fenotipo resultante
3. Inferencia de la función de la proteína diana
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“Reverse chemical genetics”
1. Generación de colecciones combinatorias (“target oriented synthesis TOS”)
2. Identificación de ligandos de la proteína diana
3. Estudios celulares en presencia del ligando
4. Determinación de la función de la proteína diana
Observe phenotypic changes to determine protein function
¿Cuáles son los ligandos una proteína?
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La identificación de ligando(“small-molecule microarrays”)
Ma, H.; Horiuchi, K. Y., Chemical microarray: a new tool for drug screening and discovery. Drug Discov. Today 2006, 11, 661-668.
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La identificación de ligando(“small-molecule microarrays”)
Spring, D. R., Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev 2005, 34, 472-482.
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La identificación de ligando (“surface plasmon resonance”) (Assay Drug Dev Technol 2004, 2, 407-415)
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Uso de fragmentos como ligandos(“fragment screening”)
Fragment screening: An approach to hit or lead
identification based on the selection of fragments (small
molecules with low MW).
Drug-like molecules can be regarded as the result of the
combination of two or more individual binding epitopes or
fragments.
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The “rule of three” in fragment screening
Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R.Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004, 3, 660-672.
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Carr, R. A.; et al., Fragment-based lead discovery: leads by design. Drug Discov Today 2005, 10, 987-992.
Ligand efficiency in fragment screening
La optimización de fragmentos es más adecuada que la de “HTS hits” para llegar a compuestos que cumplan la regla de Lipinski
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Methods used for fragment screening
Carr, R. A.; et al., Fragment-based lead discovery: leads by design. Drug Discov Today 2005, 10, 987-992.
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Fragment screening (FS) vs HTS
Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R.Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004, 3, 660-672.
HTS: Suitable forforward chemical genetics
FS: Suitable for reverse chemical genetics
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Aproximaciones al “fragment screening”
Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R., Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004, 3, 660-672.
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Aproximaciones al “fragment screening”
Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R., Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004, 3, 660-672.
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Aproximaciones al “fragment screening”
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Aproximaciones al “fragment screening”
Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R., Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004, 3, 660-672.