chemistry

Lipinski's rule of five

Lipinski's rule of five is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Lipinski's rule of five rather than just read about it. In short: 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.

Key takeaways

Lipinski's rule of five belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Lipinski's rule of five to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Lipinski's rule of five from memory before moving on to harder problems.

Reference excerpt

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. 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. 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.

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 filters 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 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:

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. 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. As a result, it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during hit and lead optimization. To solve this problem, 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. 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

External links 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

Illustrations

Worked examples

Example 1 — a first encounter with Lipinski's rule of five

Start with the simplest possible case. Write down what Lipinski's rule of five claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Lipinski's rule of five before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Lipinski's rule of five ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Lipinski's rule of five

In research: Lipinski's rule of five appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Lipinski's rule of five in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Lipinski's rule of five is common in secondary-school and first-year university syllabi. It links to neighbouring topics Cheminformatics, Drug development, Drug discovery, so understanding it makes those chapters shorter.
In everyday life: Look for Lipinski's rule of five outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Lipinski's rule of five in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Lipinski's rule of five means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Lipinski's rule of five out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Lipinski's rule of five in simple terms?

Why does Lipinski's rule of five matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Lipinski's rule of five?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Lipinski's rule of five.