introduction to ligand- based drug design chimica ......rino ragno: computational medicinal...
TRANSCRIPT
![Page 1: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/1.jpg)
![Page 2: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/2.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 2
![Page 3: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/3.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 3
![Page 4: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/4.jpg)
Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 409-09-2015
Conformational Search Molecular Docking Simulate Annealing
Molecular Dynamics Graphical Visualization 3-D QSAR Pharmacophore
Ab Initio QM
QSAR, COMBINE, Scoring Functions, Homology Modeling,…..
![Page 5: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/5.jpg)
Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 509-09-2015
Basic Research
Target Ident
Target Valid
Hit Ident
Hit to Lead
Lead Opt Preclin Clinical
Trial Prod Diagnos
Drug Design = Computational & Synthesis Tandem
![Page 6: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/6.jpg)
Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 609-09-2015
Protein Structure
Unknown Known
Liga
nd S
truc
ture U
nkno
wn
Library Screening De Novo
Know
n
Ligand Based Structure-Based
![Page 7: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/7.jpg)
Ligand-Based
QSAR Phamacophore 3-D QSAR
Structure-Based
ScoringFunctionDocking
COMBINE
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 7
![Page 8: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/8.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 8
![Page 9: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/9.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 9
![Page 10: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/10.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 10
![Page 11: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/11.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 11
![Page 12: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/12.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 12
![Page 13: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/13.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 13
![Page 14: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/14.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 14
![Page 15: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/15.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 15
![Page 16: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/16.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 16
The Hansch Equation
![Page 17: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/17.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 17
The first QSAR equations were based on the observation that partition coefficients, as expressed by log P values, are to some
extent, correlated to certain biological endpoints.
log (1/C) = k1 log P + k2σ + k3
Conc. of compound requiredto produce a standard response
in a given t
Logarithm of the molecule’s partition coefficient
(1-octanol/water)
Hammet Parameter(molecule’s electronic
characteristics)
![Page 18: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/18.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 18
![Page 19: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/19.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 19
![Page 20: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/20.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 20
![Page 21: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/21.jpg)
Identification of Active Ligands
Identification of Suitable Descriptors (molecular fingerprint)
Establish Mathematical Expression Relating Descriptors to Activity
Construction and Validation of the QSAR model
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 21
![Page 22: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/22.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 22
![Page 23: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/23.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 23
![Page 24: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/24.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 24
Squared CorrelationCoefficient R2 or r2
Cross-Validated R2 Q2 or q2
∑
∑
=
=
−
−−= N
ii
N
iicalci
YY
YYr
1
2exp,
1
2,exp,
2
)(
)(1
∑
∑
=
=
−
−−= N
ii
N
iipredi
YY
YYq
1
2exp,
1
2,exp,
2
)(
)(1
![Page 25: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/25.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 25
Squared CorrelationCoefficient R2 or r2
∑
∑
=
=
−
−−= N
ii
N
iicalci
YY
YYr
1
2exp,
1
2,exp,
2
)(
)(1
10 2 ≤≤ r
∑
∑
=
=
−
−−≡−≡= N
ii
N
iicalci
YY
YY
TSSRSS
TSSESSr
1
2exp,
1
2,exp,
2
)(
)(11
Fitting
![Page 26: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/26.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 26
Cross-validated R2 Q2 or q2
12 ≤≤∞− q∑
∑
=
=
−
−−= N
ii
N
iipredi
YY
YYq
1
2exp,
1
2,exp,
2
)(
)(1
The predictive ability of a model is estimatedusing a reduced set of structural data
CV (Cross-Validation)
N
YYSDEP
N
iipredi∑
=
−= 1
2,exp, )(
![Page 27: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/27.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 27
![Page 28: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/28.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 28
Y-Scrambling
Scrambling
Scrambled Y vector
A new model is obtained for such permuted data, R2 and Q2 are then recalculated.This step is repeated for a sufficient number of times (iterations):
a good number being 50 to 100.
Values obtained in the above fashion are compared with the true values obtained for the modelthat was fitted on the real data.
Original X block
A statistical test of prediction tools, in which models are fitted for randomly reorderedproperty/activity values and compared with the model obtained for the actualproperty/activity values.
A new model is obtained for suchpermuted data, R2 and Q2 are thenrecalculated.This step is repeated for a sufficientnumber of times (iterations):
a good number being 50 to 100.
Values obtained in the above fashion arecompared with the true values obtained forthe model that was fitted on the real data.
Original Y vector
![Page 29: Introduction to Ligand- Based Drug Design Chimica ......Rino Ragno: Computational Medicinal Chemistry Applications to Epigenetic Targets Inhibitors 09-09-2015 5 Basic Research Target](https://reader030.vdocuments.site/reader030/viewer/2022040114/5e23a4d0bfe7cd13e62dd29b/html5/thumbnails/29.jpg)
Chimica FarmaceuticaIntroduction to Ligand-Based Drug Design 29
N
YYSDEP
N
iipredi∑
=
−= 1
2,exp, )(
N° of predicted compounds
External Test-SetSDEP (Standard Deviation Error of Prediction)