Lipinski's rule of five
Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would likely make it an orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most orally administered drugs are relatively small and moderately lipophilic molecules.[1][2]
The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion ("ADME"). However, the rule does not predict if a compound is pharmacologically active.
The rule is important to keep in mind during drug discovery when a pharmacologically active lead structure is optimized step-wise to increase the activity and selectivity of the compound as well as to ensure drug-like physicochemical properties are maintained as described by Lipinski's rule.[3] Candidate drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market.[2][4]
Some authors have criticized the rule of five for the implicit assumption that passive diffusion is the only important mechanism for the entry of drugs into cells, ignoring the role of transporters. For example, O'Hagan and co-authors wrote as follows:[5]
This famous "rule of 5" has been highly influential in this regard, but only about 50 % of orally administered new chemical entities actually obey it.
Studies have also demonstrated that some natural products break the chemical rules used in Lipinski filters such as macrolides and peptides.[6][7][8]
Components of the rule
Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:[9]
- No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
- No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
- A molecular mass less than 500 daltons
- A calculated octanol-water partition coefficient (Clog P) that does not exceed 5
Note that all numbers are multiples of five, which is the origin of the rule's name. As with many other rules of thumb, such as Baldwin's rules for ring closure, there are many exceptions.
Variants
In an attempt to improve the predictions of druglikeness, the rules have spawned many extensions, for example the Ghose filter:[10]
- Partition coefficient log P in −0.4 to +5.6 range
- Molar refractivity from 40 to 130
- Molecular weight from 180 to 480
- Number of atoms from 20 to 70 (includes H-bond donors [e.g. OHs and NHs] and H-bond acceptors [e.g. Ns and Os])
Veber's Rule further questions a 500 molecular weight cutoff. The polar surface area and the number of rotatable bonds has been found to better discriminate between compounds that are orally active and those that are not for a large data set of compounds.[11] In particular, compounds which meet only the two criteria of:
- 10 or fewer rotatable bonds and
- Polar surface area no greater than 140 Å2
are predicted to have good oral bioavailability.[11]
Lead-like
During drug discovery, lipophilicity and molecular weight are often increased in order to improve the affinity and selectivity of the drug candidate. Hence it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during hit and lead optimization. Hence it has been proposed that members of screening libraries from which hits are discovered should be biased toward lower molecular weight and lipophilicity so that medicinal chemists will have an easier time in delivering optimized drug development candidates that are also drug-like. Hence the rule of five has been extended to the rule of three (RO3) for defining lead-like compounds.[12]
A rule of three compliant compound is defined as one that has:
- octanol-water partition coefficient log P not greater than 3
- molecular mass less than 300 daltons
- not more than 3 hydrogen bond donors
- not more than 3 hydrogen bond acceptors
- not more than 3 rotatable bonds
See also
- Biopharmaceutics Classification System
- Chemical structure
- Chemicalize.org § List of the predicted structure based properties
- Fragment-based lead discovery
- QSAR
References
- ↑ "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings". Advanced Drug Delivery Reviews 46 (1–3): 3–26. March 2001. doi:10.1016/S0169-409X(00)00129-0. PMID 11259830.
- ↑ 2.0 2.1 "Lead- and drug-like compounds: the rule-of-five revolution". Drug Discovery Today: Technologies 1 (4): 337–341. December 2004. doi:10.1016/j.ddtec.2004.11.007. PMID 24981612.
- ↑ "Is there a difference between leads and drugs? A historical perspective". Journal of Chemical Information and Computer Sciences 41 (5): 1308–1315. 2001. doi:10.1021/ci010366a. PMID 11604031.
- ↑ "The influence of drug-like concepts on decision-making in medicinal chemistry". Nature Reviews. Drug Discovery 6 (11): 881–890. November 2007. doi:10.1038/nrd2445. PMID 17971784.
- ↑ "A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs". Metabolomics 11 (2): 323–339. 2015. doi:10.1007/s11306-014-0733-z. PMID 25750602.
- ↑ "Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates". Chemistry & Biology 21 (9): 1115–1142. September 2014. doi:10.1016/j.chembiol.2014.08.013. PMID 25237858.
- ↑ "Predicting cell-penetrating peptides using machine learning algorithms and navigating in their chemical space". Scientific Reports 11 (1): 7628. April 2021. doi:10.1038/s41598-021-87134-w. PMID 33828175. Bibcode: 2021NatSR..11.7628D.
- ↑ "Drug discovery beyond the rule of 5 - Opportunities and challenges". Expert Opinion on Drug Discovery 12 (2): 115–119. February 2017. doi:10.1080/17460441.2017.1264385. PMID 27883294.
- ↑ "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings". Advanced Drug Delivery Reviews 46 (1–3): 3–26. March 2001. doi:10.1016/S0169-409X(00)00129-0. PMID 11259830.
- ↑ "A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases". Journal of Combinatorial Chemistry 1 (1): 55–68. January 1999. doi:10.1021/cc9800071. PMID 10746014.
- ↑ 11.0 11.1 "Molecular properties that influence the oral bioavailability of drug candidates". Journal of Medicinal Chemistry 45 (12): 2615–2623. June 2002. doi:10.1021/jm020017n. PMID 12036371.
- ↑ "A 'rule of three' for fragment-based lead discovery?". Drug Discovery Today 8 (19): 876–877. October 2003. doi:10.1016/S1359-6446(03)02831-9. PMID 14554012.
External links
- Interactive Rule of Five calculator
- Free online calculations of Hydrogen bond donor/acceptor, mass and logP using ChemAxon's Marvin and Calculator Plugins – requires Java
- Calculation of Druglikeness – requires Java
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