Macrocycle bRo5 Property Profile: Sirolimus and Azithromycin
Inspect the physicochemical descriptor profiles of clinical macrocycles, starting from sirolimus (rapamycin, MW 914.19 Da), with azithromycin as a comparator you add, that operate far beyond classical Rule-of-Five thresholds. This reference explains how macrocyclisation restricts conformational entropy and why static 2D TPSA overstates exposed polarity for chameleonic macrocycles.
Opens sirolimus (CHEMBL413, a 31-membered macrolide) from the shipped ChEMBL 37 library in the comparison section. Azithromycin (CHEMBL529, 15-membered) is the suggested comparator; the address cannot pre-load a second molecule, so it is added there.
Understand how macrocycles achieve oral absorption above 700 Daltons
Natural products and semi-synthetic macrocycles such as sirolimus, tacrolimus, cyclosporine and azithromycin routinely violate two or three Lipinski thresholds, often exceeding 750 Da in molecular weight and 150 Ų in topological polar surface area (sirolimus 914 Da and 195 Ų, azithromycin 749 Da and 180 Ų by RDKit), yet achieve clinically useful oral bioavailability. Their large ring architectures allow them to engage flat, extended protein–protein interaction surfaces or ribosomal tunnels that compact 350 Da small molecules cannot span.
Once azithromycin is added beside sirolimus in the comparison, notice where both compounds sit on the PCA chemical-space map of approved drugs: they populate the high-mass, high-TPSA outer periphery while keeping hydrogen-bond donor counts (HBD) relatively restrained compared with their acceptor counts.
Distinguish 2D topological descriptors from 3D exposed polarity
Because hydrogen-bond donors carry a severe desolvation penalty when unshielded, successful oral macrocycles typically cap excess NH groups via N-methylation or position them to form intramolecular hydrogen bonds across the ring. Always complement 2D descriptor inspection with experimental chromatographic logD, lipophilic permeability and metabolic stability measurements.
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)
Topological polar surface area
TPSA = Σ Ai
- Ai
- Polar fragment contribution assigned by the descriptor method (Ų)
- TPSA
- Topological estimate from the represented molecular graph (Ų)
Macrocyclic ring constraint on rotatable bonds
Nrot,macrocycle < Nrot,linear-seco-analogue
- Nrot,macrocycle
- Strict rotatable-bond count where bonds inside the macrocyclic ring are excluded
- Nrot,linear-seco-analogue
- Rotatable-bond count of the corresponding open-chain linear precursor
Scope and limitations
- The RDKit strict rotatable-bond definition treats all ring bonds, including the 15- and 31-membered rings here, as non-rotatable, even though large rings retain internal torsional degrees of freedom.
- Static 2D TPSA sums every polar nitrogen and oxygen fragment and cannot model solvent-dependent intramolecular hydrogen-bond networks (chameleonicity) that lower effective 3D polar surface area in apolar media.
- The single-conformer MMFF94s+ 3D view does not sample the solvent-dependent conformational ensemble of a large macrocycle.
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
- Doak et al.: oral druggable space beyond the Rule of 5: insights from drugs and clinical candidatesCited method; bRo5 physicochemical boundaries
- Whitty et al.: quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugsCited method; solvent-dependent 3D PSA vs 2D TPSA
Technical questions
Why does closing a linear peptide or polyketide into a macrocycle improve membrane permeability?
Ring closure pre-organises the backbone and eliminates the terminal ends, reducing the conformational entropy penalty upon membrane partitioning and shielding amide or ester bonds from proteolytic degradation.
What is chameleonic behaviour in a beyond-Rule-of-5 macrocycle?
A chameleonic macrocycle changes its three-dimensional conformation depending on solvent polarity: in water, it exposes polar hydrogen-bond donors and acceptors to maintain aqueous solubility, whereas inside a lipid membrane it folds inward to form intramolecular hydrogen bonds that mask its polar surface area.
Why does a macrocycle often show a surprisingly low RDKit rotatable-bond count?
Because standard graph-based rotatable-bond definitions exclude all bonds that belong to a ring, closing a 20-bond chain into a ring drops those backbone bonds out of Nrot. When comparing macrocycles, inspect heavy-atom count, ring size and peripheral side-chain rotatable bonds rather than relying on Nrot alone.
Connected workflows
- Lipinski rule-of-five property inspection
Compare sirolimus with the tacrolimus beyond-Rule-of-Five reference.
- Whole-molecule PROTAC property inspection
Contrast cyclic bRo5 macrocycles with linear heterobifunctional PROTAC degraders.
- DMSO stock reconstitution volume
Account for high macrocycle molecular weight when preparing millimolar stocks.