patrick an introduction to medicinal chemistry 3/e chapter 10 drug design:
DESCRIPTION
Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 2: Section 10.2. Contents Part 2: Sections 10.2 3.Pharmacophore 3.1.Structural (2D) Pharmacophore (7 slides) 3.2.3D Pharmacophore (6 slides) - PowerPoint PPT PresentationTRANSCRIPT
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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal
ChemistryChemistry 3/e 3/e
Chapter 10Chapter 10
DRUG DESIGN: DRUG DESIGN: OPTIMIZING TARGET OPTIMIZING TARGET
INTERACTIONSINTERACTIONS
Part 2: Section 10.2Part 2: Section 10.2
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ContentsContents
Part 2: Sections 10.2
3. Pharmacophore3.1. Structural (2D) Pharmacophore (7 slides)3.2. 3D Pharmacophore (6 slides)3.3. Generalised Bonding Type Pharmacophore3.4. The Active Conformation 3.5. Pharmacophores from Target Binding Sites 3.6. Pharmacophoric Triangles
[20 slides]
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DRUG DESIGN AND DEVELOPMENTDRUG DESIGN AND DEVELOPMENT
StagesStages
1) Identify target disease1) Identify target disease 2) Identify drug target2) Identify drug target 3) Establish testing procedures3) Establish testing procedures 4) Find a lead compound4) Find a lead compound 5) Structure Activity Relationships (SAR)5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore6) Identify a pharmacophore 7) Drug design- optimising target interactions7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests9) Toxicological and safety tests10) Chemical development and production10) Chemical development and production11) Patenting and regulatory affairs11) Patenting and regulatory affairs12) Clinical trials12) Clinical trials
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3. PHARMACOPHORE3. PHARMACOPHORE
• Defines the important groups involved in bindingDefines the important groups involved in binding
• Defines the relative positions of the binding groupsDefines the relative positions of the binding groups
• Need to know Active ConformationNeed to know Active Conformation
• Important to Drug DesignImportant to Drug Design
• Important to Drug DiscoveryImportant to Drug Discovery
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3.1 Structural (2D) Pharmacophore3.1 Structural (2D) Pharmacophore
Defines minimum skeleton connecting important binding groups Defines minimum skeleton connecting important binding groups
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O
NMe
HO
HO
MORPHINE
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O
NMe
HO
HO
MORPHINE
IMPORTANT GROUPS FOR ANALGESIC ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY
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O
NMe
HO
HO
MORPHINE
IMPORTANT GROUPS FOR ANALGESIC ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY
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N
HO
ANALGESIC PHARMACOPHORE FOR OPIATESANALGESIC PHARMACOPHORE FOR OPIATES
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MORPHINE
O
NMe
HO
HO
NMe
HO
LEVORPHANOL
NMe
HO
METAZOCINE
CH3
H3C
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MORPHINE
O
NMe
HO
HO
NMe
HO
LEVORPHANOL
NMe
HO
METAZOCINE
CH3
H3C
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3.2 3D Pharmacophore3.2 3D Pharmacophore
Defines relative positions in space of important binding groups Defines relative positions in space of important binding groups
ExampleExample
N
HO
HO
N
x
x
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O
NMe
HO
HO
MORPHINE
IMPORTANT GROUPS FOR ACTIVITYIMPORTANT GROUPS FOR ACTIVITY
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O
NMe
HO
HO
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OO
NN
ArAr
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OO
NN
ArAr
11.3o
150o
18.5o
7.098 A
2.798 A
4.534 A
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Defines relative positions in space of the binding interactions Defines relative positions in space of the binding interactions which are required for activity / bindingwhich are required for activity / binding
3.3 Generalised Bonding Type Pharmacophore3.3 Generalised Bonding Type Pharmacophore
Ar
Ar
x
x
y
BaseHBA
HBDHBA Base
HBA
HBDHBA
y
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3.4 The Active Conformation3.4 The Active Conformation
• Need to identify the active conformation in order to identify the Need to identify the active conformation in order to identify the 3D pharmacophore 3D pharmacophore
• Conformational analysis - identifies possible conformations and Conformational analysis - identifies possible conformations and their activities their activities
• Conformational analysis is difficult for simple flexible Conformational analysis is difficult for simple flexible molecules with large numbers of conformationsmolecules with large numbers of conformations
• Compare activity of rigid analoguesCompare activity of rigid analogues
NH2HO HO NH2 HO
NH2
HO HO HO
I II
rotatable bonds
Dopamine
Locked bondsLocked bonds
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3.5 Pharmacophores from Target Binding Sites3.5 Pharmacophores from Target Binding Sites
H-bonddonor oracceptor
aromaticcenter
basic orpositive center
H-bonddonor oracceptor
aromaticcenter
basic orpositive center
Pharmacophore
OH
CO2
ASP
SER
PHE
Bindingsite
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3.6 Pharmacophoric Triangles3.6 Pharmacophoric Triangles
HO
NH2
HO
Pharmacophore triangles for dopaminePharmacophore triangles for dopamine
HO
NH2
HO
HO
NH2
HO
ArAr
Basic
HBD/HBA
HBD/HBA