Part 2. Physicochemical Properties 1.Rules ( 양혜란 ) 2.Liphophilicity ( 백아름 ) 3.pKa ( 박숙진 ) 4.Solubility ( 전종수, 최영재 ) 5.Permeability ( 김소연, 강경태 )

4. Rules for Rapid Property Profiling from Structure Lee,Sang-Hwi

4.1 Lipinski’s rules of 5 ① MW < 500 ② logP < 5 (or MlogP < 4.15), M : Moriguchi method ③ < 5 H-bond donors (expressed as the sum of all OHs and NHs) ④ < 10 H-bond acceptors (expressed as the sum of all Ns and Os) * Good absorption or permeation conditions ※ Hydrogen bonds increase solubility in water and must be broken in order for the compound to permeate into and through the lipid bilayer membrane. Lipinski

Nature Reviews Drug Discovery 6: 29-40

MW is related to the size of the molecules As molecular size increases, a larger cavity must be formed in water in order to solubilize the compound, and solubility decreases. Increasing MW reduces the compound concentration at the surface of the intestinal epithelium, thus reducing absorption. Increasing size also impedes passive diffusion through the tightly packed aliphatic side chains of the bilayer membrane. Increasing Log P also decreases aqueous solubility, which reduces absorption. Finally, membrane transporters can either enhance or reduce compound absorption by either active uptake transport or efflux, respectively. Thus, transporters can have a strong impact on increasing or decreasing absorption. MW / Molecular size / Log P : (↑) Solubility / Absorption : (↓)  Molecular size : Molecular weight, Electron density, Polar surface area, Van der Waals surface, Molar refractivity

4.2 Veber Rules ① ≤10 rotatable bonds  reduced molecular flexibility ② ≤140 Å 2 PSA (polar surface area) ③ ≤12 total hydrogen bonds (acceptors plus donors) ● For good oral bioavailability in rats are as follows:  Doxorubicin: very low bioavailability (BA 5%) to correlate very well with the human intestinal absorption, caco-2 mono layers permeability, and blood-brain barrier penetration (≤ 60 Å 2 PSA) Rotatable bonds were defined as any single bond, not in a ring, bound to a nonterminal heavy (i.e., non-hydrogen) atom. Excluded from the count were amide C-N bonds because of their high rotational energy barrier.

Lead-likenessDrug-likeness 어떤 약물이 임상 1 상 완료까지 살아 남을 만큼 용인 할 만한 ADME 특성과 독성적인 특성을 함께 가지는 약물 MW<350<500 Lipophilicity<3<5 HBD<3<5 HBA<8<10 PSA(Å 2 )<120<150 Rotatable bond<8<10

Problems