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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 In English, the phrase ''rule of thumb'' refers to an approximate method for doing something, based on practical experience rather than theory. This usage of the phrase can be traced back to the 17th century and has been associated with various t ...
to evaluate druglikeness or determine if a
chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
with a certain
pharmacological Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
or
biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
has
chemical properties A chemical property is any of a material's properties that becomes evident during, or after, a chemical reaction; that is, any quality that can be established only by changing a substance's chemical identity.William L. Masterton, Cecile N. Hurley, ...
and
physical properties A physical property is any property that is measurable, whose value describes a state of a physical system. The changes in the physical properties of a system can be used to describe its changes between momentary states. Physical properties are ...
that would make it a likely
orally active Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...
drug in humans. The rule was formulated by
Christopher A. Lipinski Christopher A. Lipinski is a medicinal chemist who is working at Pfizer, Pfizer, Inc. He is known for his Lipinski's rule of five, "rule of five", an algorithm that predicts drug compounds that are likely to have oral activity. By the number of ci ...
in 1997, based on the observation that most orally administered drugs are relatively
small Small may refer to: Science and technology * SMALL, an ALGOL-like programming language * Small (anatomy), the lumbar region of the back * ''Small'' (journal), a nano-science publication * <small>, an HTML element that defines smaller text ...
and moderately
lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and b ...
s. The rule describes molecular properties important for a drug's
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
in the human body, including their
absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which s ...
,
distribution Distribution may refer to: Mathematics * Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a vari ...
,
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
, and
excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after ...
("
ADME ADME is an abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug level ...
"). However, the rule does not predict if a compound is pharmacologically active. The rule is important to keep in mind during
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...
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. Candidate drugs that conform to the RO5 tend to have lower attrition rates during
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s and hence have an increased chance of reaching the market. 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:
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 filter such as macrolides and peptides


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: * No more than 5
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
donors (the total number of
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...
and
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
–hydrogen bonds) * No more than 10
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
acceptors (all
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
or
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
atoms Every atom is composed of a nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has no neutrons. Every solid, liquid, gas ...
) * A
molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quant ...
less than 500
dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit * John Dalton, chemist, physicist and meteorologist Entertainment * Dalton (Buffyverse), minor ch ...
s * A calculated
octanol-water partition coefficient The ''n''-octanol-water partition coefficient, ''K''ow is a partition coefficient for the two-phase system consisting of ''n''-octanol and water. ''K''ow is also frequently referred to by the symbol P, especially in the English literature. It is a ...
(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 In English, the phrase ''rule of thumb'' refers to an approximate method for doing something, based on practical experience rather than theory. This usage of the phrase can be traced back to the 17th century and has been associated with various t ...
, such as
Baldwin's rules Baldwin's rules in organic chemistry are a series of guidelines outlining the relative favorabilities of ring closure reactions in alicyclic compounds. They were first proposed by Jack Baldwin in 1976. Baldwin's rules discuss the relative rates ...
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: *
Partition coefficient In the physical sciences, a partition coefficient (''P'') or distribution coefficient (''D'') is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solub ...
log ''P'' in −0.4 to +5.6 range *
Molar refractivity Molar refractivity,W. Foerst et.al. ''Chemie für Labor und Betrieb'', 1967, ''3'', 32-34. https://organic-btc-ilmenau.jimdo.com/app/download/9062135220/molrefraktion.pdf?t=1616948905 A, is a measure of the total polarizability of a mole of a subs ...
from 40 to 130 * Molecular weight from 180 to 480 * Number of atoms from 20 to 70 (includes H-bond donors .g. OHs and NHsand H-bond acceptors .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 in the rat. 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.


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 lipophility 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. A rule of three compliant compound is defined as one that has: * octanol-water
partition coefficient In the physical sciences, a partition coefficient (''P'') or distribution coefficient (''D'') is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solub ...
log ''P'' not greater than 3 *
molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quant ...
less than 300
dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit * John Dalton, chemist, physicist and meteorologist Entertainment * Dalton (Buffyverse), minor ch ...
s * not more than 3
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
donors * not more than 3
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
acceptors * not more than 3 rotatable bonds


See also

*
Biopharmaceutics Classification System The Biopharmaceutics Classification System is a system to differentiate the drugs on the basis of their solubility and permeability. This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility ...
*
Chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...
* *
Fragment-based lead discovery Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in mole ...
* QSAR


References

{{reflist, colwidth=35em, refs= {{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 {{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 {{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 {{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 {{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 {{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 {{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


External links


Interactive Rule of Five calculator


using ChemAxon's Marvin and Calculator Plugins – requires Java
Calculation of Druglikeness
– requires Java Medicinal chemistry Pharmaceutical industry Cheminformatics Drug discovery Rules of thumb