Lipinski's Rule of Five
Encyclopedia
Lipinski's Rule of Five is a rule of thumb
to evaluate druglikeness
or determine if a chemical compound
with a certain pharmacological
or biological activity
has properties that would make it a likely orally active drug
in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication
drugs are relatively small and lipophilic molecule
s.
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 for drug development
where a pharmacologically active lead structure
is optimized step-wise for increased activity and selectivity, as well as drug-like properties as described by Lipinski's rule.
Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:
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 guidelines for ring closure or Murphy's guidelines), there are many exceptions to Lipinski's Rule.
better, the rules have spawned many extensions, for example one from a 1999 paper by Ghose et al.:
Over the past decade Lipinski's profiling tool for druglikeness
has led to further investigations by scientists to extend profiling tools to lead-like properties of compounds in the hope that a better starting point in early discovery can save time and cost. Some compound searching sites, such as the extensive searching tools on the ASDI website, now allow using Rule-of-5 and other properties to rapidly identify compounds that may be more desirable for high throughput screening and for parallel synthesis efforts.
Rule of thumb
A rule of thumb is a principle with broad application that is not intended to be strictly accurate or reliable for every situation. It is an easily learned and easily applied procedure for approximately calculating or recalling some value, or for making some determination...
to evaluate druglikeness
Druglikeness
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested...
or determine if a chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
with a certain pharmacological
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
or biological activity
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 pharmacophore but can be modified by the other...
has properties that would make it a likely orally active drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
drugs are relatively small and lipophilic molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s.
The rule describes molecular properties
Molecular property
Molecular properties include the chemical properties, physical properties, and structural properties of molecules, including drugs. Molecular properties typically do not include pharmacological or biological properties of a chemical compound.- See also :...
important for a drug's pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
in the human body, including their absorption
Absorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
, distribution
Distribution (pharmacology)
Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of drug from one location to another within the body....
, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, and excretion
Excretion
Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. 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 leaving the cell...
("ADME
ADME
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
"). However, the rule does not predict if a compound is pharmacologically active.
The rule is important for drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
where a pharmacologically active lead structure
Drug discovery hit to lead
Early drug discovery involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead...
is optimized step-wise for increased activity and selectivity, as well as drug-like properties as described by Lipinski's rule.
Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:
- Not more than 5 hydrogen bondHydrogen bondA hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
donors (nitrogenNitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
or oxygenOxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
atoms with one or more hydrogenHydrogenHydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atoms) - Not more than 10 hydrogen bondHydrogen bondA hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
acceptors (nitrogenNitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
or oxygenOxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
atoms) - A molecular massMolecular massThe molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
not greater than 500 daltonAtomic mass unitThe unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
s - An octanol-water partition coefficientPartition coefficientIn chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...
log P not greater than 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 guidelines for ring closure or Murphy's guidelines), there are many exceptions to Lipinski's Rule.
Improvements
To evaluate druglikenessDruglikeness
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested...
better, the rules have spawned many extensions, for example one from a 1999 paper by Ghose et al.:
- Partition coefficientPartition coefficientIn chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...
log P in -0.4 to +5.6 range - Molar refractivity from 40 to 130
- Molecular weight from 160 to 500
- 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])
- Polar surface area no greater than 140 Ǻ2
Over the past decade Lipinski's profiling tool for druglikeness
Druglikeness
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested...
has led to further investigations by scientists to extend profiling tools to lead-like properties of compounds in the hope that a better starting point in early discovery can save time and cost. Some compound searching sites, such as the extensive searching tools on the ASDI website, now allow using Rule-of-5 and other properties to rapidly identify compounds that may be more desirable for high throughput screening and for parallel synthesis efforts.
See also
- QSAR, quantitative structure-activity relationship
- Polar surface areaPolar surface areaThe polar surface area of a molecule is defined as the surface sum over all polar atoms, primarily oxygen and nitrogen, also including their attached hydrogens....
- Biopharmaceutics Classification SystemBiopharmaceutics Classification SystemThe Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration . The fundamental basis for the BCS was established by Dr...
- Chemical propertyChemical propertyA chemical property is any of a material's properties that becomes evident during a chemical reaction; that is, any quality that can be established only by changing a substance's chemical identity...
- Molecular propertyMolecular propertyMolecular properties include the chemical properties, physical properties, and structural properties of molecules, including drugs. Molecular properties typically do not include pharmacological or biological properties of a chemical compound.- See also :...
- Physical propertyPhysical propertyA physical property is any property that is measurable whose value describes a physical system's state. The changes in the physical properties of a system can be used to describe its transformations ....
- Chemical structureChemical structureA chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
- Chemicalize.orgChemicalize.orgchemicalize.org is a free chemical structure miner and web search engine developed and owned by ChemAxon. The main purpose of chemicalize.org is to identify chemical names on websites and convert them to chemical structures...
: List of predicted structure based properties
External links
- Interactive Rule of Five calculator
- Free online calculations of Hydrogen bond donor/acceptor, mass and logP using ChemAxonChemaxonChemAxon is a software company specializing in application programming interfaces and end user applications for cheminformatics and life science research...
's Marvin and Calculator Plugins - requires Java - Calculation of Druglikeness - requires Java