The rule of five states that molecules that violate two or more of the following rules are likely to have permeability problems; (1) CLOGP calculated octan-1-ol-water log P greater than 5.0; (2) molecular weight greater than 500; (3) more than five hydrogen bond donors; and (4) the sum of oxygen and nitrogen atoms is greater than 10.
Notes: - Natural products, peptides and other substrates for biological transporters are exceptions.
- The original authors also noted that one can calculate the octan-1-ol-water log P with the program MLOGP for which the cut-off is \(\pu{4.15}\). Users often use log P’s calculated with other programs or measured values.
Source:
PAC, 2016, 88, 239. 'Glossary of terms used in computational drug design, part II (IUPAC Recommendations 2015)' on page 255 (https://doi.org/10.1515/pac-2012-1204)