Julia Salas

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• Julia Salas
• CS379a
• 2-28-06

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Aim of the Study

• To determine distinguishing features of orally
  administered drugs
• Physical and structural features probed
• Druglike Molecules with desirable
  pharmacokinetic and pharmacodynamic (PK/PD)
  properties
• Pharmacokinetics Absorbtion, distribution,
  metabolism, and elimination (ADME)
• Pharmacodynamics Mechanism of drug action,
  dosage, mechanism, etc

Pharmacodynamics is the study of what a drug does
to the body, whereas pharmacokinetics is the
study of what the body does to a drug
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Compounds Surveyed

• Three sets of compounds used
• 1. Known drugs (Marketed Drugs) 1,729
• 1193 with oral formulation (good PK/PD)
• 536 without oral formulation (poor PK/PD)
• Injectable (308), topical (112), and absorbent
  (116)
• 2. Clinical candidates 1,817
• 3. SAR compounds 113,937
• Biologically active but not druggable

Molecular properties and structural fragments
were analyzed
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Methods Structural Fragments

• Chemical Fragments Molecular Slicer (MS)
• Tool to deconstruct molecules into scaffolds and
  side chain fragments

Side Chain Fragment
Scaffold Fragment
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Methods Physical Properties

• Molecular weight (MW)
• Atom count (NATOM)
• Calculated Log of octanol-water partition
  coefficient (CLOGP)
• Tendency to prefer a non-aqueous or oily
  environment rather than water
• (A measure of lipophilicity)
• Rotatable bonds (ROT)
• Rings (NRING)
• Nitrogens and oxygens (ONs)
• H-bond acceptors (ACC)
• H-bond donors (DON)
• Polar surface area (PSA)
• Surface area (SA)
• Halogens (halogen)
• What are the Most Relevant Druglike Properties?

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Physical Properties Determining Relevance

• Correlations observed for the 1,729 marketed
  drugs
• PSA correlates with ON count, SA correlates with
  MW,
• NATOM correlates with MW, DON correlates with
  NHOH count
• Relevant MW, ON, OHNH, ACC, NRING, ROT, HALOGEN,
  CLOGP

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Physical PropertiesControlling for (Oral) Drug
Approval Date
Although the nature and location of drug targets
have changed, mean physical properties of the
drugs have not
Inflammation/Asthma Cardiovascular Central
Nervous System Hormones Infectious
Disease Metabolic Disease
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Oral Drugs vs. Nonoral Drugs Physical Properties

• Trends agree with a previously published study

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Oral Drugs vs. Nonoral Drugs Physical Properties
Property distribution means, medians, and
p-values were calculated for the mean values of
the oral drugs with the other groups

• Injectables are more polar, heavier, and more
  flexible
• Higher mean MW, ON, OHNH, NRING, ROT, H-bond
  acceptors and lower CLOGP and halogens
• Absorbents and Topicals are most similar to oral
  drugs
• Absorbents have (slightly) lower CLOGP and
  (slightly) higher OHNH counts
• Topicals have (slightly) different MW, NRINGS,
  halogens, CLOGP

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Common Fragments of Oral vs. Injectable
DrugsSide Chains
Oral
Injectable

• Several sidechains found in both groups
• The means of the 8 properties are similar

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Common Fragments of Oral vs. Injectable
DrugsScaffolds
Oral
Injectable

• Injectables More polar and flexible
• ON count, ROT, CLOGP show same trends as whole
  molecule

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Conclusions

• Differences in physical properties lie in the
  scaffolds (not side chains) of molecules
• Oral drugs have lower MW, balanced CLOGP, and
  greater rigidity
• Knowledge of trends in scaffolds and physical
  properties may be applied to future searches for
  oral drug candidates

We cannot accurately classify a particular drug
as either oral or injectable on the basis of
simple physical property calculations