Fsp3 Calculator: Fraction sp3 Carbons and 3D Saturation
Calculate the fraction of sp³-hybridised carbons (Fsp3) and aromatic ring count for a chemical structure, then inspect a seeded MMFF94s+ 3D conformer in the browser. This reference loads amantadine (Fsp3 = 1.00) alongside planar aromatic comparators to examine how saturation and ring planarity relate to crystal packing and developability.
Uses the shipped ChEMBL 37 amantadine parent SMILES (CHEMBL660), a fully saturated tricyclic adamantane amine where all ten carbon atoms are sp³-hybridised.
Balance sp² cross-coupling convenience against sp³ three-dimensionality
Palladium-catalysed Suzuki–Miyaura and Buchwald–Hartwig cross-couplings make flat sp²-rich biaryl and heteroaromatic libraries easy to synthesise in parallel, which historically enriched screening decks in planar molecules with low Fsp3 and three or more aromatic rings. Lovering et al. observed that average Fsp3 and chiral-centre counts increased steadily as compounds progressed from discovery through clinical phases to approval, while Ritchie and Macdonald showed that keeping aromatic ring count at or below three reduces the risk of poor solubility, CYP inhibition and hERG binding.
Amantadine illustrates the opposite extreme in the workspace: its rigid tricyclic adamantane cage has zero aromatic rings and an Fsp3 of 1.00. Comparing its 3D conformer and PCA chemical-space position with flat heteroaromatic kinase inhibitors makes the contrast between sp³ cage geometry and planar ring systems concrete.
Inspect Fsp3 alongside logP, aromatic rings and stereocentres
Replacing a phenyl ring with a saturated bioisostere, such as a piperidine, morpholine, cyclobutyl or bicyclo[1.1.1]pentane unit, simultaneously increases Fsp3, reduces aromatic ring count and disrupts crystal stacking. Always check how that replacement shifts cLogP and basicity, and preserve defined stereochemical wedges when introducing new chiral sp³ centres.
Equations and variables
Fraction of sp³-hybridised carbon atoms
Fsp3 = nC,sp3 / nC,total
- nC,sp3
- Count of tetrahedral sp³-hybridised carbon atoms in the represented molecular graph
- nC,total
- Total count of carbon atoms in the molecule (0 if the structure contains no carbon)
- Fsp3
- Dimensionless carbon saturation fraction ranging from 0 (completely unsaturated/aromatic) to 1
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)
Scope and limitations
- Fsp3 is a 2D hybridization ratio; an acyclic alkyl chain has Fsp3 = 1.0 for its carbons yet remains conformationally flexible rather than forming a rigid 3D scaffold.
- Higher Fsp3 or chiral centre counts do not automatically confer target selectivity or aqueous solubility if accompanied by high lipophilicity (logP).
- The 3D viewer generates one seeded MMFF94s+-minimised conformer in vacuum, which does not represent the Boltzmann-weighted solution ensemble or protein-bound geometry.
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
- Lovering, Bikker and Humblet: Escape from Flatland: increasing saturation as an approach to improving clinical successCited method; Fsp3 and chiral-centre progression analysis
- Ritchie and Macdonald: the impact of aromatic ring count on compound developabilityCited method; aromatic ring count liabilities
Technical questions
How is Fsp3 calculated, and do heteroatoms count in the denominator?
Fsp3 is defined strictly on carbon atoms: it divides the number of sp³-hybridised carbons by the total number of carbons in the molecule. Nitrogen, oxygen and sulfur atoms do not enter the numerator or denominator, although they influence polarity (TPSA) and hydrogen bonding separately.
Why do molecules with four or more aromatic rings often show poor aqueous solubility?
Flat, conjugated biaryl and polyaromatic systems pack efficiently via π–π stacking in the solid crystal lattice, raising the melting point and the energetic cost of crystal lattice disruption required for aqueous dissolution, in addition to increasing lipophilicity.
What is the average Fsp3 of approved small-molecule drugs in the ChEMBL 37 library?
Across the 2,197 approved parent small molecules in the shipped ChEMBL 37 dataset, the mean Fsp3 is 0.437 (with a standard deviation of 0.257) and the mean aromatic ring count is 1.56, reflecting a balance between heteroaromatic recognition motifs and saturated aliphatic or alicyclic rings.
Connected workflows
- Structural edits and property comparison
Explore how replacing an aromatic ring with a saturated ring alters descriptors.
- TPSA and Crippen logP calculation
Check how heteroatom incorporation in saturated rings shifts TPSA and logP.
- DMSO stock reconstitution volume
Prepare DMSO stock solutions while tracking crystal-packing solubility limits.