Lipinski Rule of Five Checker

Enter molecular weight, LogP, H-bond donors, and H-bond acceptors to evaluate a compound's drug-likeness using Lipinski's Rule of Five. A compound passes if it violates at most one rule: MW ≤ 500, LogP ≤ 5, HBD ≤ 5, HBA ≤ 10. These guidelines predict oral bioavailability for small molecule drugs.

Molecular Weight (Da)

Rule: ≤ 500 Da

XLogP (Lipophilicity)

Rule: ≤ 5.0

H-Bond Donors (HBD)

Rule: ≤ 5 (NH + OH groups)

H-Bond Acceptors (HBA)

Rule: ≤ 10 (N + O atoms)

Lipinski's Rule of Five

Published by Christopher Lipinski in 1997, the Rule of Five (Ro5) provides a set of empirical guidelines for predicting whether a drug candidate is likely to be orally bioavailable. The four rules state that a drug-like molecule should have: a molecular weight no greater than 500 daltons, a calculated octanol-water partition coefficient (XLogP or cLogP) no greater than 5, no more than 5 hydrogen bond donors (OH and NH groups), and no more than 10 hydrogen bond acceptors (N and O atoms). Violations of more than one rule strongly predict poor gastrointestinal absorption or membrane permeability.

The underlying rationale links each parameter to passive transcellular diffusion across the intestinal epithelium. High molecular weight reduces membrane permeability; excessive lipophilicity (high LogP) leads to poor aqueous solubility despite good membrane permeation; too many hydrogen bond donors and acceptors impose a high desolvation energy cost that hinders membrane crossing. Together, these four physicochemical parameters explain a large fraction of the variance in human oral bioavailability data across diverse drug classes.

Important exceptions exist for drugs that rely on active transport rather than passive diffusion. Antibiotics such as erythromycin, antifungals like itraconazole, and many natural product-derived drugs routinely violate one or more Ro5 criteria yet achieve acceptable oral bioavailability through carrier-mediated uptake. The "beyond Rule of Five" (bRo5) space — occupied by macrocycles and PROTACs — represents a growing area of drug discovery where Ro5 predictions are less reliable, and PAMPA permeability or Caco-2 assays are preferred for experimental bioavailability assessment.

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This content is for educational and informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider before making medication decisions.

Data sources: ChEMBL, PubChem, DailyMed.

How to Use

1
Enter a SMILES or molecule identifier
Input a SMILES (Simplified Molecular Input Line Entry System) string or an international chemical identifier such as InChI or CAS number for the drug molecule of interest. The checker resolves the structure and computes key molecular descriptors using cheminformatics algorithms validated against published datasets.
2
Evaluate Lipinski Rule of Five parameters
The tool calculates molecular weight (MW), calculated octanol-water partition coefficient (cLogP), hydrogen bond donor count (HBD), and hydrogen bond acceptor count (HBA). Each parameter is compared against Lipinski's Rule of Five thresholds to predict oral bioavailability likelihood.
3
Review additional ADMET predictions
Beyond the Rule of Five, the tool computes topological polar surface area (TPSA) and rotatable bond count, and provides Veber's criteria for oral absorption. Results are interpreted in the context of exceptions to the Rule of Five relevant to natural product-derived drugs and high-permeability active transporter substrates.

About

Lipinski's Rule of Five represents one of the most influential contributions to computational medicinal chemistry, establishing quantitative physicochemical thresholds that predict the likelihood of adequate oral bioavailability based on passive intestinal permeability and aqueous solubility. Published by Christopher Lipinski and colleagues at Pfizer using analysis of 2,245 drugs in the World Drug Index, the rules capture the physicochemical constraints imposed by the gastrointestinal epithelium on passive diffusion-dependent drug absorption. Their simplicity and predictive utility made them a foundational tool in pharmaceutical industry compound library design and drug candidate selection over three decades.

The importance of oral bioavailability in drug development reflects both patient preference for oral administration and the pharmacokinetic implications of incomplete absorption. Bioavailability (F) is the product of the fraction absorbed from the GI tract (Fabs), the fraction escaping intestinal wall metabolism (Fg), and the fraction escaping hepatic first-pass metabolism (Fh). Lipinski's rules primarily predict Fabs through their proxies for transcellular permeability and aqueous solubility. The fraction escaping first-pass metabolism — heavily influenced by CYP3A4 and efflux transporters in the intestinal wall and liver — depends on metabolic stability and transporter interactions not captured by Rule of Five parameters.

Contemporary drug discovery has evolved beyond simple Rule of Five compliance to apply multi-parameter optimization (MPO) approaches that simultaneously score compounds across six to ten ADMET-relevant descriptors including cLogP, molecular weight, TPSA, HBD, pKa, and solubility. This checker implements the Lipinski parameters and Veber criteria as the initial assessment layer, with results interpreted in the context of the specific target, administration route, and structural class of the molecule under evaluation.

FAQ

What are Lipinski's Rule of Five and what do they predict?

Lipinski's Rule of Five, published in Advanced Drug Delivery Reviews in 1997, empirically derived four physicochemical thresholds from analysis of FDA-approved oral drugs: molecular weight ≤500 Da, cLogP ≤5 (lipophilicity), hydrogen bond donors ≤5 (OH and NH groups), and hydrogen bond acceptors ≤10 (O and N atoms). Molecules violating two or more rules are predicted to have poor oral bioavailability. The rules apply to passive diffusion-driven permeability and are most predictive for CNS-inactive drugs absorbed by transcellular passive diffusion. They do not apply to drugs that are substrates of intestinal active transporters or compounds derived from biological fermentation, which frequently violate the rules despite good oral bioavailability.

What is topological polar surface area and why is it important?

Topological polar surface area (TPSA) is the surface sum over all polar atoms (primarily oxygen and nitrogen, including their attached hydrogens), calculated from two-dimensional molecular structure without conformational sampling. TPSA is a computationally efficient predictor of passive intestinal permeability and blood-brain barrier penetration. A TPSA of less than 140 Ų is associated with acceptable intestinal absorption, while a TPSA below 90 Ų is required for significant CNS penetration. Veber's criteria for oral bioavailability in rats add TPSA ≤ 140 Ų and rotatable bonds ≤ 10 as complementary predictors of oral absorption to the Lipinski parameters.

What is cLogP and how does it relate to drug permeability?

cLogP is the calculated logarithm of the octanol-water partition coefficient, measuring lipophilicity — the tendency of a molecule to distribute into the lipid phase relative to water. Higher cLogP values indicate greater lipophilicity and generally improve passive transcellular membrane permeability, but very high cLogP (>5) is associated with poor aqueous solubility, increased plasma protein binding, increased non-specific tissue binding, and metabolic instability. Modern medicinal chemistry practices apply the concept of LipE (lipophilic efficiency or LLE = pIC50 − cLogP) to optimize potency while minimizing excess lipophilicity, improving both selectivity and ADME properties simultaneously.

Are there important exceptions to the Rule of Five?

The Rule of Five was derived from orally administered small molecule drugs and explicitly excludes natural product-derived compounds and biologics. Many macrolide antibiotics, glycopeptides (vancomycin, MW 1449 Da), macrocyclic natural products, and cyclic peptides exceed Rule of Five thresholds yet achieve clinical oral bioavailability through mechanisms including active transport, transcytosis, and cyclization reducing the polar surface area. Beyond Rule of Five (bRo5) space is increasingly explored in modern drug discovery for targeting protein-protein interactions, undruggable targets, and macrolide-accessible intracellular pathogens. Pfizer and AstraZeneca have published analyses showing oral drugs with MW 500–1000 Da achieving clinical development if TPSA is optimized.

How is the Rule of Five used in early drug discovery?

The Rule of Five serves as a rapid oral bioavailability filter in early drug discovery, applied to large compound libraries during computational virtual screening or high-throughput screening cascade prioritization. Compounds violating the rules are either deprioritized for oral development or flagged for structural optimization by medicinal chemists to improve pharmacokinetic properties. The rule complements other computational ADMET predictions including metabolic stability, aqueous solubility (logS), plasma protein binding, CYP inhibition liability, and hERG channel inhibition. Together, these filters define a multi-parameter optimization space guiding lead optimization campaigns toward drug-like molecules suitable for clinical development.