Structure-Activity Relationships
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Structure-Activity Relationships. Drug Design. Barbiturates - . pharmacological and structural class. usually administered as salts. Modifications. Uses: sedative hypnotic antianxiety. An Antiischemic, Bradycardic Therapeutic Agent. bradycardia - slowed heartbeat.

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Barbiturates -

pharmacological and structural class

usually administered as salts


  • 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

    • don’t discount toxic side effects

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Lipinski’s 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 >10.

B.S.SF State

Ph.D. Berkeley

postdoc Cal Tech

Christopher Lipinski (Pfizer)

screened >2300 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 (<300 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 protein:ligand 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




nuclear receptors



active sites, allosteric sites, new(novel) sites


X-ray crystallography (binding)

Enthalpy Array (H of ligand binding)


SPR -plasmon resonance (kinetics of ligand binding)

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Nano-calorimetry - enthalpy array

Scripps PARC Institute

enthalpy of ligand binding

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Nano-calorimetry - enthalpy array

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Plasmon Resonance


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Improvements in IC50 and EC50

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Computer-assisted analysis of carcinogenicity


(quantitative structure-activity relationship)

(quantitative structure-property relationship)

molecular descriptors

physiochemical parameters



electron density

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Drug X

enantiomer of X

Drug X













Formulations, Durability, Optical Isomerism

physical state

physical properties

chemical stability

formulation compatibility



A,F –hydrogen bond donors

B,E– hydrogen bond acceptors

C– hydrophobic group