L’uso del computer nel drug discovery - SyMeCh · [Synthetic Medicinal Chemistry group MMlab] 1...
Transcript of L’uso del computer nel drug discovery - SyMeCh · [Synthetic Medicinal Chemistry group MMlab] 1...
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L’uso del computer nel drug discovery
Alberto Massarotti [email protected]
a.a. 2012-2013
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Le slide
www.symech.it/didattica
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L’esame
Sicuramente una domanda aperta sugli argomenti trattati
durante le lezioni
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Letture consigliate…
Molecular Modeling -- Basic Principles and Applications by H.D. Höltje, W. Sippl, Di. Rognan, G. Folkers
Molecular Modelling: Principles and Applications by Andrew Leach
Chemoinformatics in Drug Discovery by T. I. Oprea, R. Mannhold, H. Kubinyi, G. Folkers
Molecular Design: Concepts and Applications by H. Kubinyi, G. Schneider, K.H. Baringhaus
Chemoinformatics: A Textbook by J. Gasteiger, T. Engel
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“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance”
Un bit di...
Farmaco
Informatica
Progettazione
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L’evoluzione dell’informatica Sistemi Hardware 1980 Sistemi Hardware 2010
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L’informatica ci aiuta…
…a virtualizzare la realtà. (interazione legando-recettore)
…a eseguire operazioni ripetitive. (peso molecolare)
L’accuratezza è fondamentale!
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Il tempo è denaro
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La legge di Moore
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http://www.ncats.nih.gov/research/reengineering/process.html
14 anni dai 400 ai 900 milioni di dollari
….il tempo è nemico
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Claude Monet, Pagliaio, 1886. Olio su tela, 61 x 81 cm © Museo di Stato dell'Hermitage, St. Pietroburgo
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?
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I composti chimici
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http://www.cas.org http://pubs.acs.org/ http://www.ncbi.nlm.nih.gov/pubmed/
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I composti chimici
ChemistryCAS – 34 milioni
CCDC – 445000 strutture
http://www.cas.org http://www.ccdc.cam.ac.uk
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Kirkpatric P., Ellis C., Nature 2004, 432, 823
C H O N P
P.M. < 500 ?
1060
molecole
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1060 molecole = 1000000000000000000000000000000000000000000000000000000000000
CAS database = 34 milioni di molecole = 34000000
Kirkpatric P., Ellis C., Nature 2004, 432, 823 http://www.cas.org
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Cosa ci aspettiamo dal molecular modelling
?
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
Angoli torsionali dell’ATP
Stockwell G. R. And Thornton J. M., J. Mol. Biol. 2006, 356, 928-944
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
Olomoucina legata a CDK2 (1W0X)
Dreyer M. K., et al., J. Med. Chem. 2001, 44, 524-530
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
Conformazioni cristallizate di NAD
Stockwell G. R. And Thornton J. M., J. Mol. Biol. 2006, 356, 928-944
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
Binding del fattore Xa della coagulazione
http://bioserv.rpbs.jussieu.fr/~autin/help/index.html Nazare M., et al., J. Med. Chem. 2005 , 48, 4511
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Obiettivi
• Analisi • Visualizzazione • Confronto • Predizione • Design
Binding dell’adenina derivato dal PDB
Stockwell G. R. And Thornton J. M., J. Mol. Biol. 2006, 356, 928-944
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Dove ci inseriamo
?
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?
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?
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Ligand-based Drug Design (LBDD)
Similarity search
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?
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Virtualizzare le strutture
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Virtualizzare le strutture
Composto chimico
Struttura chimica
Proprietà chimiche
Rappresentazioni numeriche della struttura chimica
Descrittori molecolari
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Come si può archiviare un composto?
Acido acetilsalicilico
C9H8O4
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Acido acetilsalicilico
C9H8O4
Qual è la differenza nell’usare queste tre modalità?
?
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Acido acetilsalicilico
C9H8O4
Qual è la differenza nell’usare queste tre modalità?
È una semplice stringa!
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Prova cronometro: queste due rappresentazioni strutturali sono identiche?
C9H8O4 C9H8O4
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Prova cronometro: queste due rappresentazioni strutturali sono identiche?
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Come posso gestirlo?
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File .mol
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Come posso gestirlo?
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File .mol2
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Acido acetilsalicilico
C9H8O4
Cosa cambia da un punto di vista informatico?
6 byte 1299 byte 2051 byte
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SMILES (Simplified Molecular Input Line Entry Specification)
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
c1(C(=O)O)ccccc1OC(=O)C
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Codifica degli idrocarburi alifatici
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
Metano
Etano
Propano
2-metil-propano
cicloesano
C
CC
CCC
CC(C)C
C1CCCCC1
H
HHH
H
HH
H
HH
H
HH
H
HH
H H H
HH
H
HH
HH H
H
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Codifica degli idrocarburi insaturi
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
Etilene
Propene
trans (E)-2-butene
cis (Z)-2-butene
Etino o acetilene
C=C
C=CC
C/C=C/C
C/C=C\C
C#C
H
H H
H
H
H H
HH H
H
H
HH H
HHH
H H
HH H
HHH
HH
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Codifica degli idrocarburi aromatici
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
Benzene
Toulene
4-metil-anilina
Naftalene
c1ccccc1
c1ccccc1C
c1ccc(N)cc1C
c12c(cccc1)cccc2
NH2
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Codifica degli alcooli, aldeidi, chetoni e acidi
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
Etanolo
Etanale
Acetone
Acido acetico
CCO
CC=O
CC(=O)C
CC(=O)O
H
HH
O
H
HH
H
HH
O
OH
H
HH
O
H
H
HH
OH
HH
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SMILES canonici
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html H. L. Morgan, J. Chem. Doc., 1965, 5, 107; LG, S.7
CCO C(O)C
H
HH
OH
HH
CC(=O)Oc1ccccc1C(=O)O c1(C(=O)O)ccccc1OC(=O)C
- Creare un’unica stringa per ogni composto chimico - Omogeneizzare stringhe provenienti da diversi software - Facilitare le procedure di ricerca in archivi elettronici
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Archiviare le strutture
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Database di molecole
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Query
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Database di molecole
c1(C(=O)O)ccccc1OC(=O)C ?
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Database di molecole
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Torniamo al nostro ago…
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Quale potrebbe essere una strategia per trovare altri “composti attivi”?
? Abbiamo un
composto biologicamente
attivo
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Quale potrebbe essere una strategia per trovare altri “composti attivi”?
Abbiamo un composto
biologicamente attivo
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1. Queste nuove proposte molecolari esistono già nel nostro spazio chimico esplorato? 2. Si può creare un ordine di priorità di sintesi?
?
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Analizziamo lo spazio chimico
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Similarità
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Similarità
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Il paradosso della similarità
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Come confrontare le strutture?
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Frammentazione molecolare
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Regole di frammentazione
G.W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887 –2893
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Sfruttiamo i frammenti
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MACCS (Molecular ACCess System)
166
O OH
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Vi ricordate i diagrammi di Eulero-Venn?
?
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L’insieme intersezione
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Coefficiente di Tanimoto
Il coefficiente di Tanimoto indica la similarità tra due insiemi.
LJ. L. Durant, et al., JCICS 2002, 42, 1273-1280
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Coefficiente di Tanimoto
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Applicazioni
>0.85
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Applicazioni
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Applicazioni
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Applicazioni
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Limitazioni
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…pausa?
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Ligand-based Drug Design (LBDD)
Pharmacophore matching
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?
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Farmacoforo…
…già sentito?
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Berellini G., et al. Pharmacophore, Drug Metabolism, and Pharmacokinetics Models on Non-Peptide AT1, AT2, and AT1/AT2 Angiotensin II Receptor Antagonists. J. Med. Chem. 2005, 48, 4389-4399
Recettore Angiotensina II tipo 1
Predittività del 95%
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Farmacoforo… Un farmacoforo è la più piccola unità strutturale di una molecola, costituita da un
insieme di gruppi funzionali disposti opportunamente nelle tre dimensioni spaziali, che
interagendo specificatamente con un recettore è responsabile dell’attività biologica.
Ad es.
- Don. legame idrogeno
- Acc. legame idrogeno
- Zone idrofobiche Leach A. R. et al., J. Med. Chem. 2010, 53, 539-558
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Proviamo a generarlo…
?
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Ipotesi farmacoforica
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Ipotesi farmacoforica
sicuri?
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L’equilibrio tautomerico
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L’equilibrio conformazionale
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…quanti modelli abbiamo?
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…è solo un’ombra della realtà
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1. Selezionare una conformazione
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Analoghi rigidi
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Analoghi rigidi
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3. Triangolazione
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4. Dai frammenti chimici ai punti farmacoforici
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Il triangolo può essere indicizzato da una tripletta di caratteri: ACD Del triangolo posso calcolare proprietà numeriche peculiari: lunghezza dei lati, perimetro.
A
C
D
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Andiamo a pesca…
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Il pagliaio va “preparato”
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Vi ricordate il calcolo combinatorio?
?
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Vi ricordate il calcolo combinatorio?
Consideriamo un’ipotesi farmacoforica con tre punti, quanti triangoli farmacoforici si possono generare?
?
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© Tesi
Vi ricordate il calcolo combinatorio?
Consideriamo un’ipotesi farmacoforica con tre punti, quanti triangoli farmacoforici si possono generare?
ACD ADC CDA CAD DAC DCA
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Vi ricordate il calcolo combinatorio?
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?
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Limitazioni
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Esempio
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Esempio
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To do list
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