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 Inflammation/Asthma Cardiovascular Central Nervous System Hormones Infectious Disease Metabolic Disease Although the nature and location of drug targets have changed, mean physical properties of the drugs have not

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

9. 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 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

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

11. Common Fragments of Oral vs. Injectable Drugs Scaffolds 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”