Lipinski's Rule of Five (RO5 Druglikeness)

Medicinal chemistry heuristic formulated by Christopher Lipinski in 1997 to predict whether a small molecule will be orally bioavailable in humans.

Specifications & Metrics

type: Medicinal Chemistry & ADME Heuristic
symbol: RO5 (MW ≤ 500, cLogP ≤ 5, HBD ≤ 5, HBA ≤ 10)
units: Four physicochemical thresholds (multiples of 5)
equation: No more than 1 violation among: H-bond donors ≤ 5, H-bond acceptors ≤ 10, MW ≤ 500 Da, cLogP ≤ 5
pioneer: Christopher A. Lipinski, Franco Lombardo, Beryl W. Dominy, and Paul J. Feeney at Pfizer (published 1997)

Formulated in 1997 by Christopher Lipinski and colleagues at Pfizer after analyzing 2,245 compounds from the World Drug Index that had entered Phase II clinical trials, the "Rule of Five" takes its name from all four cutoffs being multiples of five.
Poor oral absorption or membrane permeation is more likely when a compound violates two or more criteria: more than 5 hydrogen-bond donors (OH and NH groups), more than 10 hydrogen-bond acceptors (N and O atoms), molecular weight over 500 Da, or octanol–water partition coefficient (cLogP) over 5.
While natural products, macrocycles (such as cyclosporine and rapamycin), and PROTAC degraders can achieve oral activity outside "beyond-Rule-of-5" space, fragment-based screening often enforces a stricter "Rule of Three" (MW < 300, cLogP ≤ 3, HBD ≤ 3, HBA ≤ 3) so leads stay within RO5 during optimization.