Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer...
Transcript of Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer...
![Page 1: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/1.jpg)
Medicinal Chemistry/ CHEM
458/658
Chapter 4- Computer-Aided
Drug Design
Bela Torok
Department of Chemistry
University of Massachusetts Boston
Boston, MA
1
![Page 2: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/2.jpg)
Computer Aided Drug Design - Introduction
• Development of computers
- hardware
- algorithms – softwares
- computation chemists
- representation
2
![Page 3: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/3.jpg)
• Models
• Molecular modelling methods
- Molecular or quantum mechanics
- Semiempirical vs ab initio methods
- Cartesian and polar coordinates
3
Computer Aided Drug Design - Introduction
![Page 4: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/4.jpg)
• Computer graphics
- space fill, CPK (Corey-Pauling-Koulton), stick, stick and ball,
mesh, ribbon, surface, molecular dinamics etc.
4
Computer Aided Drug Design - Introduction
![Page 5: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/5.jpg)
• Basis: Etotal= Σ attractive + repulsive forces
- mechanical method – atoms are “balls” with respective atomic
masses
5
Molecular Mechanics
![Page 6: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/6.jpg)
• Etotal= Σ Estretching+Σ Ebend+ΣEtorsion+ΣEvdW+ΣEcoulombic
6
Molecular Mechanics
![Page 7: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/7.jpg)
• Creating a molecular model using molecular mechanics
- Joining fragments from program database
- Prepare 2D structure and convert it to 3D structure
- Converting an existing model from the database
Molecular Mechanics
7
![Page 8: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/8.jpg)
• Creating a dynamic molecular model
- atomic coordinates (twist, bend, stretch etc.)
- conformational analysis
8
Molecular Dynamics
![Page 9: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/9.jpg)
9
• Schrodinger equation, Born-Oppenheimer approximation
- simplification – Hartree-Fock approximation
– Density Funtional Theory
Practice – Gaussian 03 (or 98) ab initio methods
– Gamess
Quantum Mechanics
John A. PopleWalter Kohn
"for his development of the density-functional theory"
"for his development of computational methods in quantum chemistry"
The Nobel Prize in Chemistry 1998
![Page 10: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/10.jpg)
10
Docking
• Produce and investigate the complex of large biomolecule (host)
and the drug (or candidate) (ligand)
• Ebinding= Etarget+ Eligand – Etarget-ligand
Global Emin ⇄ Bioactive conformer
![Page 11: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/11.jpg)
• De novo design
Using docking programs to design new lead structures
The template method
The component fragment method
11
Docking
![Page 12: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/12.jpg)
12
• A case study
Inhibition of FBPase (Kimberly Stieglitz)
Start: - build and optimize the drug candidate
ChemDraw and import to Gaussian
or get crystal structure (CCD)
- get protein (enzyme or receptor) structure
PDB
Docking
![Page 13: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/13.jpg)
13
Docking
• A case study
Inhibition of FBPase - list of compounds
![Page 14: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/14.jpg)
14
Docking
• A case study
Inhibition of FBPase - protein structure
![Page 15: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/15.jpg)
15
Docking
• A case study
Inhibition of FBPase - docking
![Page 16: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/16.jpg)
16
![Page 17: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/17.jpg)
17
Docking
• A case study
Inhibition of FBPase - visualization
![Page 18: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/18.jpg)
Docking
18
![Page 19: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/19.jpg)
Docking
19
![Page 20: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/20.jpg)
Docking
20
![Page 21: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/21.jpg)
21
Comparing 3D Structure by Overlays
![Page 22: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/22.jpg)
22
Comparing 3D Structure by Overlays
![Page 23: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/23.jpg)
23
![Page 24: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/24.jpg)
Pharmacophores
24
A case study
Inhibition of AChE - Marianna Torok, Seema Bag
![Page 25: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/25.jpg)
Typical pharmacophore features are:
- Hydrophobic
- Aromatic
- Hydrogen bond donor/acceptor
- Cation/anion
Pharmacophores
The features need to match different chemical groups with
similar properties, in order to identify novel ligands.
Ligands receptor interactions are typically “polar positive”,
“polar negative” or “hydrophobic”.
A well-defined pharmacophore model includes both
hydrophobic volumes and hydrogen bond vectors.
25
![Page 26: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/26.jpg)
Pharmacophores
Select molecules: 50 – 100 highly active molecules
Training set + test set
PHASE
Version 3.0
Create pharmacophoricsites
Prepare Ligands
Find common pharmacophore using
binary decision tree
Alignment
Build QSAR model r2 & q2
value
Screen/design for more potent
analogs
26
![Page 27: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/27.jpg)
Pharmacophores
Pharmacophoric points on active molecules
27
![Page 28: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/28.jpg)
Pharmacophores
Interpretation
H-donor Hydrophobic
28
![Page 29: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/29.jpg)
Pharmacophores
29
![Page 30: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/30.jpg)
Pharmacophores
galanthamine dihydrocodein
morphine 30
![Page 31: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/31.jpg)
31
![Page 32: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/32.jpg)
Modeling Protein Structures
32
Solvent Mapping (Sandor Vajda, BU)
16 solvents:
ethanol, acetaldehyde, acetonitrile,
benzaldehyde, isopropanol, methanol,
dimethyl ether, urea, benzene,
t-butanol, isobutanol, cyclohexane,
methanamine, acetamide, phenol, acetone,
dimethylformamide and ethane)
will be used in rigid-body fragment
docking
![Page 33: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/33.jpg)
Modeling Protein Structures
33
![Page 34: Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer ...alpha.chem.umb.edu/.../Lecture_Chapter_4.pdf · Medicinal Chemistry/ CHEM 458/658 Chapter 4- Computer-Aided Drug Design ...](https://reader036.fdocuments.us/reader036/viewer/2022062317/5f0f88e77e708231d444a484/html5/thumbnails/34.jpg)
34