Lipinski Rule of Five Calculator and bRo5 Inspection
Inspect the tacrolimus parent structure as a beyond-rule-of-five reference, then compare its properties with smaller compounds in the same workspace. The rule summaries describe a set of molecular descriptors. They are useful prompts for medicinal-chemistry review, but they do not decide whether a molecule can be a drug.
A large macrocyclic compound in the shipped ChEMBL 37 library. It provides a concrete exception to treating simple property thresholds as universal drug-approval rules. The reference comparison pairs tacrolimus with imatinib, a smaller kinase inhibitor from the same library; this is chemical-space context rather than a controlled absorption experiment.
Use thresholds as questions to investigate
Molecular weight, lipophilicity and hydrogen-bonding capacity can help organise a discussion about solubility and membrane passage. They compress a complex structure into a few numbers, losing information about conformation, ionisation, intramolecular hydrogen bonding and active transport. The tacrolimus reference makes that loss of information visible: a large macrocycle cannot be fully described by a threshold count.
Inspect each property before reading the combined rule result. A compound just above a threshold is not separated by a biological discontinuity from one just below it. Measurement conditions and model choices also matter. A descriptor boundary is a convention in a screening framework, so the underlying value and its method are more informative than a pass/fail colour alone.
Compare chemical space with a stated purpose
The approved-drug library offers context, not a training set that proves a new molecule will succeed. Its selection includes parent structures and heterogeneous routes of administration. A neighbour by fingerprint similarity may have different ionisation or formulation requirements. Distinguish similarity of represented chemical graphs from similarity of pharmacology or exposure.
When evaluating a series, use consistent molecular forms and retain measured solubility, permeability and exposure as separate endpoints. A property change can guide which experiment to run next, while an assay result tests a specific hypothesis. If a series is intentionally beyond the classical rule space, document that rationale and choose measurements suited to its chemistry instead of modifying the thresholds until every compound receives a favourable label.
Equations and variables
Average molecular weight
MW = Σ ni Mi
- ni
- Count of atoms of element i in the represented structure
- Mi
- Average atomic mass used by the engine (g/mol)
- MW
- Molar mass of the represented structure (g/mol)
Implemented rule-of-five checks
MW ≤ 500; Crippen logP ≤ 5; historical HBD ≤ 5; historical HBA ≤ 10
- MW
- Average molecular weight (g/mol)
- Crippen logP
- Computed neutral-species partition estimate
- historical HBD
- Hydrogens attached to nitrogen or oxygen in the historical count
- historical HBA
- Nitrogen and oxygen atom count used by this rule implementation
Scope and limitations
- The implementation distinguishes historical Lipinski donor/acceptor counts from RDKit donor/acceptor-site descriptors. Do not silently exchange those definitions.
- Crippen logP is the implemented estimate, not an experimental partition measurement or the proprietary CLOGP algorithm.
- Macrocycles, transport substrates and other beyond-rule-of-five compounds can depart from the heuristic. A violation is not an efficacy, safety or developability verdict.
Sources and provenance
- RDKit descriptor implementation and versioned reference checksBSD-3-Clause
Method implementation; computed molecular properties are estimates.
- ChEMBL 37 parent structures in the shipped compound libraryCC BY-SA 3.0; share-alike
Existing library capture: 28 September 2026. Preserve attribution when redistributing its rows.
- Wildman and Crippen: atomic contributions to molecular propertiesCited method; no reproduced article data
- Ertl, Rohde and Selzer: fast calculation of molecular polar surface areaCited method; no reproduced article data
- Lipinski et al.: experimental and computational approaches to estimate solubility and permeabilityCited method; no reproduced article data
Technical questions
Does failing a rule mean a molecule cannot be orally active?
No. The rule is an empirical screening heuristic with a defined historical context. Some compounds outside its bounds have useful exposure through mechanisms or conformational behaviour that these simple descriptors do not capture. Investigate the relevant properties experimentally rather than turning the count into a universal rejection rule.
Why are there two donor or acceptor counts?
The workspace distinguishes the historical counts used in its Lipinski rule from modern RDKit site-count definitions. Their numbers can differ for certain functional groups. A comparison is only meaningful when the same definition is applied to each compound.
Can I compare tacrolimus with a kinase inhibitor?
Yes, as a descriptive comparison in the existing workspace. It illustrates different chemical space, not a controlled experiment on absorption. Record the represented forms and descriptor methods, and avoid attributing a pharmacokinetic difference to one property without supporting data.
Connected workflows
- Whole-molecule PROTAC property inspection
Inspect another class that often occupies high-mass chemical space.
- TPSA and Crippen logP calculation
Read the methods behind two commonly compared descriptors.
- CNS property inspection and MPO limitations
See why CNS optimisation needs more than a rule-of-five result.
- US incretin listed-patent inspection
Separate structural heuristics from regulatory and legal status.
- Veber Rules Calculator: Rotatable Bonds and TPSA ≤ 140 Ų
Add the Veber rotatable-bond and polar-surface checks beside the Rule of Five.
- Fragment Rule of Three (Ro3) Descriptors and Lead-Likeness
Apply the tighter fragment Rule of Three to a smaller starting point.