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Julia Salas CS379a 2-28-06

Julia Salas CS379a 2-28-06. 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

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Julia Salas CS379a 2-28-06

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  1. Julia Salas CS379a 2-28-06

  2. 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

  3. 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

  4. Methods: Structural Fragments Chemical Fragments & Molecular Slicer (MS) • Tool to deconstruct molecules into scaffolds and side chain fragments Side Chain Fragment Scaffold Fragment

  5. 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?

  6. 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

  7. Physical Properties:Controlling 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

  8. Oral Drugs vs. Nonoral Drugs: Physical Properties • Trends agree with a previously published study

  9. 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

  10. Common Fragments of Oral vs. Injectable DrugsSide Chains • Several sidechains found in both groups • The means of the 8 properties are similar Oral Injectable

  11. Common Fragments of Oral vs. Injectable DrugsScaffolds • Injectables: More polar and flexible • ON count, ROT, CLOGP show same trends as whole molecule Oral Injectable

  12. 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”

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