Editing Lipinski's rule of five

{{Short description|Rule of thumb to predict if a chemical compound is likely to be an orally active drug}}
{{redirect|Rule of five|the rule of thumb as it applies to the C++11 programming language|Rule of five (C++ programming)}}
{{Use dmy dates|date=September 2020}}
'''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 [[pharmacology|pharmacological]] or [[biological activity]] has [[chemical property|chemical properties]] and [[Physical property|physical properties]] that would likely make it an [[Bioavailability|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 molecule|small]] and moderately [[lipophilicity|lipophilic]] [[molecule]]s.<ref name="Lipinski_1997"/><ref name="Lipinski_2004"/>

The rule describes [[molecular property|molecular properties]] important for a drug's [[pharmacokinetics]] in the human body, including their [[Absorption (pharmacology)|absorption]], [[distribution (pharmacology)|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 [[drug discovery hit to lead|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.<ref name="Oprea_2001"/> Candidate drugs that conform to the RO5 tend to have lower attrition rates during [[clinical trial]]s and hence have an increased chance of reaching the market.<ref name="Lipinski_2004"/><ref name="Leeson_2007"/>
[[File:Omeprazole.svg|thumb|[[Omeprazole]] is a popular drug that conforms to Lipinski's rule of five.]]

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:<ref name= "Hagan" /><blockquote>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.</blockquote>

Studies have also demonstrated that some natural products break the chemical rules used in Lipinski filters such as macrolides and peptides.<ref>{{cite journal | vauthors = Doak BC, Over B, Giordanetto F, Kihlberg J | title = Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates | journal = Chemistry & Biology | volume = 21 | issue = 9 | pages = 1115–1142 | date = September 2014 | pmid = 25237858 | doi = 10.1016/j.chembiol.2014.08.013 | doi-access = free }}</ref><ref>{{cite journal | vauthors = de Oliveira EC, Santana K, Josino L, Lima E, Lima AH, de Souza de Sales Júnior C | title = Predicting cell-penetrating peptides using machine learning algorithms and navigating in their chemical space | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 7628 | date = April 2021 | pmid = 33828175 | pmc = 8027643 | doi = 10.1038/s41598-021-87134-w | bibcode = 2021NatSR..11.7628D }}</ref><ref>{{cite journal | vauthors = Doak BC, Kihlberg J | title = Drug discovery beyond the rule of 5 - Opportunities and challenges | journal = Expert Opinion on Drug Discovery | volume = 12 | issue = 2 | pages = 115–119 | date = February 2017 | pmid = 27883294 | doi = 10.1080/17460441.2017.1264385 | doi-access = free }}</ref>

== 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:<ref>{{cite journal | vauthors = Lipinski CA, Lombardo F, Dominy BW, Feeney PJ | title = Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings | journal = Advanced Drug Delivery Reviews | volume = 46 | issue = 1–3 | pages = 3–26 | date = March 2001 | pmid = 11259830 | doi = 10.1016/S0169-409X(00)00129-0 }}</ref>
* No more than 5 [[hydrogen bond]] donors (the total number of [[nitrogen]]–[[hydrogen]] and [[oxygen]]–hydrogen [[chemical bond|bonds]])
* No more than 10 [[hydrogen bond]] acceptors (all [[nitrogen]] or [[oxygen]] [[atoms]])
* A [[molecular mass]] less than 500 [[atomic mass unit|dalton]]s
* 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:<ref name="Ghose_1999"/>
* [[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.<ref name="pmid12036371">{{cite journal | vauthors = Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD | title = Molecular properties that influence the oral bioavailability of drug candidates | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 12 | pages = 2615–2623 | date = June 2002 | pmid = 12036371 | doi = 10.1021/jm020017n | citeseerx = 10.1.1.606.5270 }}</ref> In particular, compounds which meet only the two criteria of:
* 10 or fewer rotatable bonds and
* Polar surface area no greater than 140 Å<sup>2</sup>
are predicted to have good oral bioavailability.<ref name="pmid12036371"/>

== 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 [[chemical library|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.<ref name="Congreve_2003"/>

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 [[atomic mass unit|dalton]]s
* 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]]
* {{section link|Chemicalize.org|List of the predicted structure based properties}}
* [[Fragment-based lead discovery]]
* [[QSAR]]

== References ==
{{reflist|colwidth=35em|refs=

<ref name="Congreve_2003">{{cite journal | vauthors = Congreve M, Carr R, Murray C, Jhoti H | title = A 'rule of three' for fragment-based lead discovery? | journal = Drug Discovery Today | volume = 8 | issue = 19 | pages = 876–877 | date = October 2003 | pmid = 14554012 | doi = 10.1016/S1359-6446(03)02831-9 }}</ref>

<ref name="Ghose_1999">{{cite journal | vauthors = Ghose AK, Viswanadhan VN, Wendoloski JJ | title = 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 = Journal of Combinatorial Chemistry | volume = 1 | issue = 1 | pages = 55–68 | date = January 1999 | pmid = 10746014 | doi = 10.1021/cc9800071 }}</ref>

<ref name="Leeson_2007">{{cite journal | vauthors = Leeson PD, Springthorpe B | title = The influence of drug-like concepts on decision-making in medicinal chemistry | journal = Nature Reviews. Drug Discovery | volume = 6 | issue = 11 | pages = 881–890 | date = November 2007 | pmid = 17971784 | doi = 10.1038/nrd2445 | s2cid = 205476574 }}</ref>

<ref name="Lipinski_1997">{{cite journal | vauthors = Lipinski CA, Lombardo F, Dominy BW, Feeney PJ | title = Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings | journal = Advanced Drug Delivery Reviews | volume = 46 | issue = 1–3 | pages = 3–26 | date = Jan 1997 | pmid = 11259830 | doi = 10.1016/S0169-409X(00)00129-0 }}</ref>

<ref name="Lipinski_2004">{{cite journal | vauthors = Lipinski CA | title = Lead- and drug-like compounds: the rule-of-five revolution | journal = Drug Discovery Today: Technologies | volume = 1 | issue = 4 | pages = 337–341 | date = December 2004 | pmid = 24981612 | doi = 10.1016/j.ddtec.2004.11.007 }}</ref>

<ref name="Oprea_2001">{{cite journal | vauthors = Oprea TI, Davis AM, Teague SJ, Leeson PD | title = Is there a difference between leads and drugs? A historical perspective | journal = Journal of Chemical Information and Computer Sciences | volume = 41 | issue = 5 | pages = 1308–1315 | year = 2001 | pmid = 11604031 | doi = 10.1021/ci010366a }}</ref>

<ref name = "Hagan">{{cite journal | vauthors = O Hagan S, Swainston N, Handl J, Kell DB | title = A 'rule of 0.5' for the metabolite-likeness of approved pharmaceutical drugs | journal = Metabolomics | volume = 11 | issue = 2 | pages = 323–339 | date = 2015 | pmid = 25750602 | pmc = 4342520 | doi = 10.1007/s11306-014-0733-z | doi-access = free }}</ref>

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== External links ==
* [https://web.archive.org/web/20070404073952/http://www.chemaxon.com/demosite/marvin/index.html Free online calculations of Hydrogen bond donor/acceptor, mass and logP] using [[ChemAxon]]'s Marvin and Calculator Plugins – requires Java
* [https://www.organic-chemistry.org/prog/peo/ Calculation of Druglikeness] – requires Java
{{Medicinal chemistry}}
[[Category:Medicinal chemistry]]
[[Category:Drug development]]
[[Category:Cheminformatics]]
[[Category:Drug discovery]]
[[Category:Rules of thumb]]