Recap:

1

• Recap
• Intermolecular forces and binding
• Overview of classes of targets for drugs
• Quantitation of
• Drug activity (functional assay) EC50, ED50, IC50
• Drug binding (binding titration) KD, KI
• Most common lab techniques (many)
• Receptors - we covered radioligand binding assay
• Enzymes - kinetics used (later in quarter)

2
Back to drug discovery

• Choose a disease/condition
• Choose a drug target
• Inferred from action of drug, poison, natural
  product, chemical signal found in humans
  revealed through genomics
• Unique to a species or tissue
• May require multiple targets for effective
  treatment
• Choose a bioassay
• In vivo, in vitro high throughput screening
• Two idealized approaches
• Start with a known lead compound (isolate,
  purify, identify)Pharmacophore-based approach
• Start with a known target structure (isolate,
  purify, identify)Target-based approach
• Hopefully, information about both lead and target
  are determined.

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Pharmacophore-based drug design

• 0. Determine identity of a lead compound
• Screen natural and synthetic banks of compounds
  for activity
• Folk medicine
• Natural ligand
• Drug already known
• Computer-aided drug design
• Computerized search of structural databases

1. Data collection Publications patents
biological activity NMR and X-ray data
physiochemical properties
Determine the effects of structural changes on
activity of drug structure-activity
relationships (SARs)
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Pharmacophore-based drug design
2. Analysis integrate information about drug
(and target) to generate hypothesis about activity
This information will result in the
identification of a pharmacophore
Pharmacophore A specific 3D arrangement of
chemical groups common to active molecules and
essential to their biological activities
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Pharmacophore-based drug design
3. Design new structures.
If you know the pharmacophore for your target,
you can create new lead compounds based on the
pharmacophore!

• Why make new lead compounds?
• Increase activity (make binding stronger)
• Decrease side effects (increase selectivity)
• Improve ease and efficiency of administration to
  patient
• Potentially find a better synthetic route

Approach Molecular mimicry.
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Pharmacophore-Based Drug Design
Simple example 1 3D structures are known 1.
Data collection biological activity of lead
compound (and other compounds)
2. Analysis biologically active molecules share
the same pharmacophoric features (superimpose 3D
structuresfind common features)
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Pharmacophore-Based Drug Design
Simple example 1 3D structures are known
3. Design new structures. New molecular mimic
will be tested.
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Pharmacophore-Based Drug Design
Example 2 (A more typical example) Biologically
active conformations are not known.
1. Data collection biological activity. Two
molecules below show good activity.
Data collection Determination of biologically
active conformation
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Pharmacophore-Based Drug Design
Example 2 (cont)
Data collection Determination of biologically
active conformation

• If no 3D data are available, use computers!
• Bioactive conformations are not always the most
  stable conformations, but are within about
  12kJ/mole or 3kcal/mole)

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Pharmacophore-Based Drug Design
Example 2 (cont)
Data collection Determination of biologically
active conformation

• Generate low energy conformations for each active
  molecule

Etc
A
Etc
B
2. Data analysis. Hypothesis bioactive
conformations share 3D features required for
activitySuperimpose the generated conformations
to define a pharmacophore
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Pharmacophore-Based Drug Design
Example 2 (cont)
3. Design Use this pharmacophore to design new
molecules to test

• Notes
• More rigid molecules have fewer conformations
  easier to analyze
• Flexible molecules have many conformations
  often must examine conformationally restricted
  analogs to determine bioactive conformation.
  (Move from computer to lab Chemical synthesis
  of analogs!) (Ex. GABA MC C2.5.2)
• Superimposing molecules dont look at sterics
  only think of physical properties of molecule.

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Pharmacophore-Based Drug Design
Superimposition of properties Example
Dihydrofolate and methotrexate bind to the
catalytic site of dihydrofolate reductase.
However, X-ray structures of these complexes
shows that they dont overlap as expected by
sterics
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Pharmacophore-Based Drug Design
Superimposition of properties Example, cont.
Examine electron density distribution of the
molecules
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Pharmacophore-Based Drug Design

• Design use analyzed data to design new
  compounds - hopefully with better properties
• Four Methods used to design better drugs
• Chemical modification
• Database searching
• De novo
• Manual
• These approaches generate more data, which yet
  again can be used to generate new hypotheses and
  structures, etc.

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Pharmacophore-based drug design Design method 1
Chemical modification
Goal Determine Structure- activity
relationships What functional groups are
important to biological activity?
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Pharmacophore-based drug design Design method 1
Chemical modification
Procedure Alter or remove groups using chemical
synthesis and test the activity of the altered
molecule (analog). Infer role of those groups in
binding.
Consequences of chemical modification to drug
activity in addition to altering binding
interactions metabolism of drug pharmacokinetic
s
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Pharmacophore-based drug design Design method 1
Chemical modification
Initial chemical modification simplification

• Once a biologically active compound is found, a
  common first tactic is to simplify it to
  determine the essential parts for activity.
• For complex molecules, this often leads to easier
  synthesis.
• Will not be successful if all parts of the
  molecule are needed for activity

Example ergot alkaloids like bromocriptine were
starting points for simplified synthetic analogs
shown below
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Pharmacophore-based drug design Design method 1
Chemical modification
Common alterations of compounds replacement of
groups with isosteres. Isosteres atoms or
groups of atoms which have the same valency
Examples OH isosteres SH, NH2, CH3 O
isosteres S, NH, CH2 H isostere F
If you change an O to CH2 - sterics same, but no
dipole or lone pair If you change an OH To SH -
sterics different, but still a lone pair
example
?
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Pharmacophore-based drug design Design method 1
Chemical modification
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Pharmacophore-based drug design Design method 1
Chemical modification
Common alterations of compounds replacement of
groups with bioisosteres. Bioisosteres -
different chemical groups with the same
biological activity. No restriction on sterics
and electronics, unlike classical isosteres.
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Pharmacophore-based drug design Design method 1
Chemical modification
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Pharmacophore-based drug design Design method 1
Chemical modification
Ring expansion/contractions - changes geometry
Ring variations - may add a binding interaction
with heteroatom
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Pharmacophore-based drug design Design method 1
Chemical modification
Extend structure by adding a functional group to
lead compound
Extend or contract linking chain length between
groups
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Pharmacophore-based drug design Design method 1
Chemical modification
Rigidification - limit number of possible
conformations Can help identify bioactive
conformation Locks molecule in most active
conformation - more effective
Add a ring
Add rigid groups
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Pharmacophore-based drug design Design method 1
Chemical modification
Rigidification (continued)
Add a bulky groups (but recall it may not just
affect conformaion it may affect sterics
Alter Stereochemistry usually different
stereoisomers have different activity
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Pharmacophore-based drug design Design method 1
Chemical modification
Probing specific functional groups in a molecule

• Binding role of hydroxy groups H-bond donor or
  acceptor
• Convert to
• methyl ether (no H-bond donor now maybe steric
  problem)
• an ester (no H-bond donor now poor H-bond
  acceptor maybe steric problem)

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Probing specific functional groups in a molecule
Binding role of hydroxy groups (continued)
methyl ether (no H-bond donor now still H-bond
acceptor maybe steric problem)
an ester (no H-bond donor now poor H-bond
acceptor maybe steric problem)
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Probing specific functional groups in a molecule

• Binding role of amino groups H-bond donor (if
  N-H is present) or acceptor ionic (protonation
  of N to form a salt recall pKa)
• Convert to
• amide (no protonation no H-bond acceptor now
  steric problem?)
• Tertiary amine (no H-bond donor now still H-bond
  acceptor sterics?)

• Binding role of aromatic rings, alkenes
  hydrophobic cation-pi
• Convert to
• Saturated compound (not effective overlap no pi
  system more flexible)

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Probing specific functional groups in a molecule

• Binding role of ketones H-bond acceptor
  dipole-dipole
• Convert to
• Alcohol (geometry change can weaken H-bond or
  dipole-dipole)

30
Probing specific functional groups in a molecule

• Binding role of alkyl substituents
  hydrophobics/sterics
• Convert to
• Longer (homologation) or differently-branched
  groups

Alkyl groups most easily modified are
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Probing specific functional groups in a molecule
Binding role of alkyl substituents (continued)

• Notes
• Recall impact of lipophilicity on drug transport
  through body
• Changing alkyl groups may also affect the
  preferred conformation of the molecule!

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Probing specific functional groups in a molecule
Binding role of alkyl substituents (continued)
Example Nifedipine analogs
Chemical synthesis of analogs help validate or
refute hypotheses regarding mechanism of
action/mode of binding - part of design
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Probing specific functional groups in a molecule

• Binding role of aryl substituents various/
  sterics
• Convert to
• Same substituents at different locations
• Different substituents Recall substituent
  effects in organic chem!
• Substituents may affect each others properties
  (pKa)

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Probing specific functional groups in a molecule
Binding role of aryl substituents (continued)
Example beta-adrenergic drugs, chemically
related to adrenaline and noradrenaline.
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Probing specific functional groups in a molecule

• Binding role of amides H-bond acceptor
  dipole-dipole
• Convert to
• Hydrolysis products (but will lose a piece)
  reduce (no more H-bond acceptor

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Pharmacophore-based drug design Design method 1
Chemical modification
Activity data for modified drugs leads to a
better pharmacophore
As computer analysis becomes more widespread, a
pharmacophore will be less visual and more
numerical, with numerical scoring of properties
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Pharmacophore-based drug design Design method 2
Database searching

• Use databases of known compounds no new
  synthesis!
• Be careful of multiple conformations
• Content of database is crucial

a. 3D Search for a 3D pharmacophore
Example. Protein kinase C enzymes are targets
for chemotherapeutic intervention against cancer.
The pharmacophore was deduced from active
phorbol esters like PDBU
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Pharmacophore-based drug design Design method 2
Database searching
The 3D database search led to the discovery of a
new potent protein kinase C inhibitor that is
chemically very different from the original
reference phorbol esters. Alignment of the two
Start over with this hit as a new lead
chemical modification, etc
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Pharmacophore-based drug design Design method 2
Database searching
b. 3D Shape searching on Databases - also finds
chemically different compounds, but is successful
only if the pharmacophore is also incorporated
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Pharmacophore-based drug design Design methods
34 De novo design and Manual design
Assemble disconnected functional groups
(pharmacophoric groups) with spacers with or
without computer algorithms using models or
computer modeling software
Example. 5-alpha reductase inhibitors inhibit
the metabolism of testosterone, and are used to
treat prostate hyperplasia. The steroid
structure has side effects. Replacement with
other structures should help...
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Pharmacophore-based drug design Design methods
34 De novo design and Manual design
Computer algorithm was used to obtain the
following compounds
Overlay of one hit
Other hits
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References
Patrick, G. L. An Introduction to Medicinal
Chemistry Oxford University Press New York,
NY, 2001 Silverman, R. B. The Organic Chemistry
of Drug Design and Drug Action Academic Press
San Diego, CA, 1992. Thomas, G. Medicinal
Chemistry An Introduction John Wiley and Sons,
Ltd. New York, NY, 2000. Williams, D. A.
Lemke, T. L. Foyes Principles of Medicinal
Chemistry Lippincott Williams and Wilkins, New
York, NY, 2002. Molecular Conceptor, Synergix
C1 Rational Drug Design C2 Structure
Activity Relationships E1-3 Pharmacophore-Based
Drug Design