presentazione di powerpoint · biotecnologie farmaceutiche chimica farmaceutica 65...
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Biotecnologie Farmaceutiche 2Chimica
Farmaceutica
Protein Structure
Unknown Known
Liga
nd
Str
uct
ure U
nkn
ow
n
Library Screening De Novo
Kn
ow
n
Ligand Based Structure-Based
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Ligand-Based
QSAR Phamacophore 3-D QSAR
Structure-Based
ScoringFunction
Docking
COMBINE
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 3
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Structure-Based
Drug Design
Approaches
3-D QSAR (Molecules aligned by SB methods)
Scoring Function (A Sort of QSARs for Molecular Docking)
COMBINE (A Full SB 3-D QSAR)
Proteochemometric (A QSAR SB derived method)
Molecular Dynamics
Pharmacophoric Approaches (Using Targets Structures)
Homology Modeling (To Build Target Structures)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 4
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Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 5
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 6
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 7
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 8
Training
Set
Molecular
Alignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internal and External
Validation
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 9
Training
Set
Molecular
lignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internal and External
Validation
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 10
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 11
Training
Set
Molecular
Alignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internal and External
Validation
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 12
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 13
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 14
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 15
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 16
Training
Set
Molecular
Alignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internal and External
Validation
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 17
Training
Set
Molecular
lignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internal and External
Validation
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 18
Training
Set
Molecular
Alignment
MolecularInteraction
Fields
(MIF)
Model
Generation
Internaland
ExternalValidation
1/2
expnyy=SDEP
pred
2
exp
2
exp
2/1 yyyy=q
pred
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Chimica FarmaceuticaThe 3-D QSAR. Application in Medicinal Chemistry 19
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The 3-D QSAR. Application in Medicinal Chemistry 20Chimica Farmaceutica
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Ricognizione molecolare: Insieme di interazioni tra molecole e
macromolecole
Modello del fitting indotto
Il sito attivo della macromolecola può essere
modificato a seconda di come interagisce il
ligando.
Daniel Koshland 1958.
Natura delle interazioni?
Intensità della ricognizione molecolare?
Modello “Lock and key”
La proteina ha una sua conformazione
all’interno del quale il ligando “fitta”
perfettamente.
Emil Fischer(1890).
Fischer E. (1894). "Einfluss der Configuration auf die Wirkung der Enzyme". Ber. Dt. Chem. Ges. 27 (3): 2985–93
Molecular Docking Pagina 21
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Ricognizione molecolareLa complementarità molecolare altamente specifica tra key (ligando) e lock
(recettore) gioca un ruolo chiave nei processi biologici.
La capacità del recettore di agganciarsi al suo ligando con alta specificità e affinità
è dovuta alla formazione di una serie di legami deboli e interazioni favorevoli.
Interazioni specifiche ligando-recettore:
COMPLEMENTARITA’ MOLECOLARE
Interazioni elettrostatiche (Non-Cov)
Forze di van der Waals (Non-Cov)
Interazioni π - π
Coordinazione con Metalli
Interazioni idrofobicheEffetti elettromagnetici
Molecular Docking Pagina 22
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Forze di van der WaalsDebole attrazione intermolecolare
causata da dipoli molecolari indotti.
Es. Interazione tra il ligando Wy-14,643 e il sito attivo della
PPARa
Quando una molecola di ossigeno si avvicina ad una
molecola di acqua orientata verso di essa con l'atomo di
ossigeno, la frazione di carica negativa presente su
quest'ultimo respinge la nuvola elettronica della molecola di
ossigeno e attira la carica positiva nucleare. Si determina
uno spostamento del baricentro della carica negativa
rispetto a quello della carica positiva nella molecola di
ossigeno e quindi induce una polarita'.
Molecular Docking Pagina 23
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In un mezzo isolante diverso dall'aria la forza F,
a parità di cariche e di distanza, risulta
generalmente minore. La forza di Coulomb si
scrive allora:
dove εr è un numero che prende il nome di
costante dielettrica relativa (permittività elettrica
relativa). Il prodotto εr x εo si indica con ε, e
si chiama costante dielettrica del mezzo
(permittività del mezzo).
Interazioni Elettrostatiche
La legge di Coulomb
d+
d d
d+
Molecular Docking Pagina 24
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Interazioni ElettrostaticheIl legame Idrogeno
ElegH (solv) – ElegH (comp)
determina se i legami-H
contribuiscono o no all’affinità
Es. Legame-H tra l’Indinavir, una molecola d’acqua e la Ile50
della proteasi dell’HIV-1 (1HSG in PDB)
LIGLIG
REC
SOLV
Molecular Docking Pagina 25
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Il fattore entropico ed entalpico nel binding
Ligando
Solvente
Recettore
Solvente
Complesso
SISTEMA:
La formazione di un complesso è guidata dal cambiamento di ENTALPIA ed
ENTROPIA del sistema
L’equazione fondamentale è:
Δ G = ΔH – TΔSdove ΔG = variazione energia libera, ΔH = variazione entalpia, ΔS = variazione
entropia, T = temperatura (K)
Molecular Docking Pagina 26
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Effetti di solvatazione
(Termine Entropico + Entalpico)
•La ricognizione molecolare tra due molecole avviene in ambiente acquoso•Le molecole di acqua mediano l’interazione attraverso ponti idrogeno•Rottura e formazione di legami-H•La desolvatazione del ligando e della proteina attraverso la complessazione è:
Sfavorevole
(Zone Elettrostatiche)• Carica del solvente
• Screening delle interazioni
elettrostatiche sulla superficie
della macromolecola
Favorevole
(zone apolari)• Cavità nel sito attivo
• Riorganizzazione delle molecole
d’acqua
• Interazioni di tipo van der Waals
tra solvente e ligando
• Gli effetti di desolvatazione sono
proporzionali all’area superficiale
accessibile
Molecular Docking Pagina 27
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Il fattore entropico nel bindingΔGbinding,solution = ΔGbinding,vacuo + ΔGsolvation(EI) - ΔGsolvation(E+I)
L’effetto idrofobico è il termine maggiormente stabilizzante per i complessi biomolecolari,
mentre le interazioni coulombiane e i legami idrogeno forniscono specificità alle
interazioni proteina-ligando.
La stabilità di un complesso può essere valutata
determinando la costante di equilibrio, che è correlata
alla variazione di energia libera:
ΔG = ΔG0 –RT ln Kd
dove ΔG0=variazione dell’energia libera in condizioni
standard, R= costante dei gas,T=temperatura assoluta, Kd
= costante di legame espressa come costante di
dissociazione con
[R] + [L] ↔ [RL]
reazione di formazione del complesso è:
Kd = [R] [L] / [RL]Kd è definita come la concentrazione del ligando per la quale il 50% dei siti
del recettore sono occupati.
Molecular Docking Pagina 28
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Il fattore entropico nel binding
Molecular Docking Pagina 29
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Il fattore entropico nel binding
Es. Aricept in soluzioneEs. Aricept nel sito attivo
della acetilcolinesterasi
I gradi di libertà “congelati” durante la complessazione rendono il
ligando sfavorito al binding
Molecular Docking Pagina 30
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Interazioni π
1. Interazioni π-π
2. Interazioni OH-π
3. Interazioni
cationi-π
Es. Interazioni π tra l’Aricept (farmaco anti-Alzheimer
approvato dalla FDA) e l’acetilcolinesterasi
Molecular Docking Pagina 31
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Coordinazione con Metalli
Legame covalente di coordinazione
S S
O O
N H
S
N H2
OO
Dorzolamide: Inibitore
dell’anidrasi carbonica,
approvato dalla FDA
come
agente anti-glaucoma
Molecular Docking Pagina 32
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DOCKING: Le Scoring Functions
Utility?•Virtual Screening
•De novo design
•Lead optimization
Molecular Docking Pagina 33
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Ligand Docking
Posa o Binding Mode: posizione, orientamento e conformazione di un
ligando sulla superficie di macromolecole biologiche
Binding Mode sperimentale: Estratta da dati cristallografici e stimata
come la migliore posa in termini di free binding energy.
Docking: Metodo computazionale utilizzato per la predizione di un
binding mode il più vicino possibile allo sperimentale (<2 Å)
Molecular Docking Pagina 34
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 35
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 36
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 38
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 39
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 45
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 46
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HDAC Inhibitors: Structure-Based Modeling and
Isoform-Selectivity Prediction
47
SAHA
X1 X2 X3 ……… Xn
X1 X2 X3 ……… Xn
X1 X2 X3 ……… Xn
…………………………………………
…………………………………………
…………………………………………
…………………………………………
…………………………………………
…………………………………………
…………………………………………
…………………………………………
…………………………………………
X1 X2 X3 ……… Xn
Cplx 1
Cplx 2
Cplx 3
…
…
…
…
…
…
…
…
…
Cplx m
Y1
Y2
Y3
…
…
…
…
…
…
…
…
…
Ym
PLS
Res1 Res2 Res3 ……… Res-n
COMBINE Model
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HDAC Inhibitors: Structure-Based Modeling and
Isoform-Selectivity Prediction
48
Proteins: Structure, Function, and Bioinformatics, 2010, 78, 135–153
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HDAC Inhibitors: Structure-Based Modeling and
Isoform-Selectivity Prediction
49
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HDAC Inhibitors: Structure-Based Modeling and
Isoform-Selectivity Prediction
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Redocking results (RMSD) with AutoDockVinaComplex
nameBest docked Best Cluster Best Fit
LLX.HDAC2 0.24 0.24 0.24
HA3.HDAC4 3.87 2.34 1.93
TMFK.HDAC4 4.02 1.9 1.46
SAHA.HDAC7 2.45 2.45 1.88
TSA.HDAC7 2.19 2.19 1.21
APHA.HDAC8 1.43 1.43 1.43
SAHA.HDAC8 2.49 2.49 1.72
TSA.HDAC8 2.09 1.22 1.22
DA % 50 75 100
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CPH M4T
ModWeb SwissModelAPHA8 in HDAC1
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CPH
M4T
ModWeb
SwissModelAPHA8 in HDAC1
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Increasing ActivityDecreasing Activity Increasing ActivityDecreasing Activity
DRY ELE
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Chimica FarmaceuticaBiotecnologie Farmaceutiche 65
Proteochemometric (PCM) modelling is a computational method to model
the bioactivity of multiple ligands against multiple related protein targets
simultaneously.
PCM modeling can be conceptualized as an extension of QSAR modeling
that exploits chemogenomic data by performing a quantitative evaluation
of ligand and target structural similarities. As a result, this technique allows
the simultaneous navigation, inter- and extrapolation in both chemical
space (i.e. ligands) and biological space (i.e. protein target). By the explicit
combination of target and ligand information in a single model PCM is
capable to analyze and predict SmARs (Structure-multiple Activity
Relationships) of a set of compounds.
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What to do if 3-D Structure of the
Target is not known?
Homology Models
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