StructureActivity Relationships

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Structure-Activity Relationships
Drug Design
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Barbiturates -
pharmacological and structural class
usually administered as salts
Modifications

• Uses
• sedative
• hypnotic
• antianxiety

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An Antiischemic, Bradycardic Therapeutic Agent
bradycardia - slowed heartbeat
ischemia - condition in which the heart is
deprived of oxygen and toxic metabolites cannot
be removed.
Ca2 very low in the cytosol.
Ca2-channels allow movement of calcium ions away
from myosin to control muscle contraction.
This drug would slow down the heart rate in order
to decrease the oxygen demand. However, it is
not desirable to lower the contractile force.
Existing calcium-channel blocking drugs, while
inducing bradycardia, also decrease the
contractile force. This can lead to congestive
heart failure.
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Therapeutic goals -
reduce heart rate, maintain contractile force,
increase duration of action
calcium-channel blocker
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Cardiac Stimulant

• Uses -
• antiarrhythmic
• prevent postmyocardial infarction

• disadvantages include
• I.V. administration (titration)
• rapid biotransformation (t1/2 1.5-2 hours)
• CNS toxicity

Therapeutic goals -

• oral administration
• longer duration
• separation of CNS toxicity from antiarrhythmia
• patentable

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• Conclusions
• increase in lipophilicity leads to an increase in
  potency
• increase in pKa leads to a decrease in toxicity
• dont discount toxic side effects

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Lipinskis Rule of 5 - a drug candidate will not
be a good candidate for oral bioavailability if

• There are more than 5 H-bond donors.
• The molecular weight is over 500.
• The LogP is over 5 (LogP refers to the
  octanol-water partition coefficient, calculated
  based on MDL's QSAR program).
• There are more than 10 H-bond acceptors.
• Number of rotatable bonds gt10.

B.S.SF State Ph.D. Berkeley postdoc Cal Tech
Christopher Lipinski (Pfizer) screened gt2300
compounds to develop the four characteristics
quickly adopted by pharmaceutical companies for
early ADME
E.B. Hersherg Award for Important Discoveries in
Medicinally Active Substances(2004) 2004 ACS
Division of Medicinal Chemistry Award
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fragment-based scaffolding
Fragments of Active Structures (FAST) - SGX
Pharmaceuticals

• Use of library of small molecule (lt300 D)
• Crystallographic screening of shape-diverse
  mixtures of fragments to identify those bound to
  the protein target of interest.
• Utilization of structurally accessible synthetic
  handles for virtual construction of linear
  elaborated libraries.
• Computational analysis of these virtual libraries
  to identify those with favorable calculated
  binding free energies.
• Linear and combinatorial library synthesis.
• Biochemical analysis followed by selection of key
  analogs for analysis with proteinligand crystal
  structures.
• Iterative synthesis of additional compounds based
  on structural, novel chemical space, and
  synthetic reasons to optimize lead series.

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fragment-based scaffolding
SGX Pharmaceuticals
Developed a library of small molecules
(fragments) used to produce lead compounds.
1400 fragments - 140 shape-diverse pools
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fragment-based scaffolding
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fragment-based scaffolding
Targets kinases phosphatases nuclear
receptors polymerases proteases
active sites, allosteric sites, new(novel) sites
Techniques X-ray crystallography
(binding) Enthalpy Array (?H of ligand
binding) Nanocalorimetry SPR -plasmon
resonance (kinetics of ligand binding)
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Nano-calorimetry - enthalpy array
Scripps PARC Institute
enthalpy of ligand binding
http//www.parc.com/research/projects/enthalpyarra
y/images/fig-01a-lg.jpg
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Nano-calorimetry - enthalpy array
http//www.parc.com/research/projects/enthalpyarra
y/images/fig-01a-lg.jpg
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Plasmon Resonance
sample
http//employees.csbsju.edu/hjakubowski/classes/ch
331/bind/olbindderveq.html
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http//www.biosensingusa.com/downloads/spranime.av
i
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Improvements in IC50 and EC50
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Computer-assisted analysis of carcinogenicity
QSAR/QSPR
(quantitative structure-activity
relationship) (quantitative structure-property
relationship)
molecular descriptors
physiochemical parameters
topological
geometry
electron density
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Formulations, Durability, Optical Isomerism
physical state
physical properties
chemical stability
formulation compatibility
receptor
receptor
A,F hydrogen bond donors B,E hydrogen bond
acceptors C hydrophobic group