Veber Rules Calculator: Rotatable Bonds and TPSA ≤ 140 Å²

Evaluate the Veber oral bioavailability descriptors, strict rotatable bond count at or below ten and topological polar surface area at or below 140 Å², for any drawn or pasted chemical structure. The workspace opens the atorvastatin parent structure so you can examine how conformational flexibility and polar surface area interact.

Uses the shipped ChEMBL 37 atorvastatin parent SMILES (CHEMBL1487), a flexible oral statin with twelve strict rotatable bonds (above the Veber limit of ten) and a TPSA of 111.8 Å² (below 140), illustrating why empirical cutoffs are prompts for review rather than hard absorption barriers.

Connect conformational flexibility and polar desolvation to permeability

Crossing a lipid bilayer by passive diffusion requires a molecule to shed its surrounding hydration shell and adopt a conformation compatible with the hydrophobic membrane interior. Topological polar surface area estimates the extent of polar nitrogen and oxygen functionality that must be desolvated, whereas the rotatable-bond count serves as a simple graph proxy for conformational entropy loss upon membrane partitioning or target binding.

Atorvastatin provides an instructive reference in the workspace: its dihydroxyheptanoic acid side chain and substituted pyrrole core contribute significant flexibility and polar surface area, yet it is a widely prescribed oral drug. Inspecting the numerical descriptors beside the approved-drug chemical-space map helps place a candidate in context rather than treating its Nrot of 12 as a sudden cliff.

Compare rigidification edits alongside experimental solubility

When a medicinal-chemistry series shows poor passive permeability in Caco-2 or PAMPA assays alongside high rotatable-bond counts, cyclising a flexible linker or replacing an acyclic chain with a ring reduces Nrot. However, excessive planar ring fusion can increase crystal packing stability and ruin aqueous solubility, so always pair Veber descriptor edits with measured kinetic and thermodynamic solubility.

Equations and variables

Implemented Veber rule checks

Nrot ≤ 10; TPSA ≤ 140 Å²

Nrot: Strict rotatable-bond count computed on the represented molecular graph
TPSA: Topological polar surface area summed over polar N and O fragments (Å²)

Topological polar surface area

TPSA = Σ Ai

Ai: Polar fragment contribution assigned by the descriptor method (Å²)
TPSA: Topological estimate from the represented molecular graph (Å²)

Scope and limitations

Veber et al. derived these thresholds from rat oral bioavailability and artificial-membrane permeation trends; they do not predict human fraction absorbed, hepatic first-pass clearance or active transporter uptake.
The RDKit strict rotatable-bond definition excludes amide C–N bonds, ring bonds and terminal methyl groups; different software packages using non-strict rules can report different bond counts on the same molecule.
Topological polar surface area is conformation-independent and does not reflect intramolecular hydrogen bonding that can shield polar groups in non-polar membranes.

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
Veber et al.: molecular properties that influence the oral bioavailability of drug candidatesCited method; rotatable bond and polar surface area thresholds

Technical questions

Why did Veber et al. highlight rotatable bonds and TPSA independently of molecular weight?

In their analysis of over one thousand drug candidates in rats, compounds with ten or fewer rotatable bonds and polar surface area at or below 140 Å² had a higher probability of achieving at least twenty percent oral bioavailability even when molecular weight exceeded 500 Da, suggesting that molecular flexibility and desolvation penalty partly explain why high-mass compounds often struggle to permeate membranes.

Which single bonds are excluded from the strict rotatable-bond count?

Terminal bonds (such as methyl –CH3, –NH2 or –CF3 groups), bonds inside rings of any size, triple bonds, and hindered amide or ester C–N/C–O bonds with partial double-bond character are excluded because their rotation does not generate distinct heavy-atom conformers.

Can an oral drug exceed 10 rotatable bonds or 140 Å² TPSA?

Yes. Atorvastatin, montelukast and several antiviral protease inhibitors are administered orally despite high rotatable-bond counts, often relying on ionisable groups, carrier-mediated transport or high potency to achieve clinical efficacy.

Connected workflows

Lipinski rule-of-five property inspection
Compare Veber flexibility and polarity criteria with Lipinski Rule of Five checks.
TPSA and Crippen logP calculation
Inspect the fragment-contribution methodology behind topological polar surface area.
DMSO stock reconstitution volume
Account for calcium or sodium salt counterions when preparing statin stock solutions.