Matched Molecular Pair (MMP) Substituent Shift Calculator
Quantify the exact physicochemical property shifts (ΔMW, ΔcLogP, ΔTPSA, ΔHBD, ΔHBA and ΔFsp3) produced by a single-point structural transformation between a reference molecule and a closely matched analogue. The workspace opens promazine, whose chlorinated matched pair chlorpromazine is in the same approved-drug library, so a single H to Cl edit can be inspected side by side.
Opens promazine (CHEMBL564) from the shipped ChEMBL 37 library. Chlorpromazine (CHEMBL71) differs only by a ring chlorine; an independent RDKit check gives ΔMW +34.45 g/mol, ΔCrippen logP +0.65 and ΔTPSA 0. The address cannot pre-load a second molecule, so chlorpromazine is added in the comparison section.
Isolate single-point substituent effects during SAR exploration
When optimising a lead series, changing three functional groups simultaneously makes it impossible to tell which modification improved potency and which one degraded metabolic stability or solubility. Organising analogues as matched molecular pairs, where only one R-group or ring atom changes at a time, turns structure–activity analysis into controlled pairwise comparisons.
In the workbench, you can retain a reference compound in the comparison panel while editing a single substituent in the structure sketcher (such as performing a methyl scan, fluoro walk or aza substitution) to read the exact ΔMW, ΔcLogP and ΔTPSA immediately.
Connect descriptor deltas to experimental potency and solubility shifts
Whenever a small substituent edit produces a potency jump far larger than its ΔcLogP would suggest (such as a two-log potency gain from a single ortho-methyl group that twists a biaryl dihedral angle), record both the calculated descriptor shift and the experimental IC50 confidence interval from the assay analyser.
Equations and variables
Matched molecular pair property shift
ΔPk = Pk(B) − Pk(A)
- A, B
- Reference structure A and modified analogue B differing by a defined structural change
- Pk
- Computed physicochemical descriptor k (MW, Crippen logP, TPSA, HBD, HBA, Nrot, Fsp3)
- ΔPk
- Exact arithmetic change in descriptor k attributable to the graph edit
Lipophilic ligand efficiency (LLE / LipE)
LLE = pIC50 − cLogP; ΔLLE = ΔpIC50 − ΔcLogP
- pIC50
- Negative base-10 logarithm of molar inhibitory potency
- cLogP
- Computed octanol–water partition estimate
- ΔLLE
- Net gain or loss in potency after subtracting the lipophilicity change
Scope and limitations
- A computed ΔcLogP from an additive fragment method (Wildman–Crippen) depends only on local atom types and cannot capture conformational shielding, ortho-substitution steric twist or intramolecular hydrogen bonding.
- Lipophilic ligand efficiency (LLE) combines an experimental assay midpoint with a calculated partition coefficient; both terms must remain separately visible so an assay artefact is not misread as a specific binding improvement.
- The workbench compares user-selected or drawn pairs and does not automatically mine a corporate database for all pairwise SMIRKS transforms.
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
- Leeson and Springthorpe: the influence of drug-like concepts on decision-making in medicinal chemistryCited method; lipophilic ligand efficiency (LLE) framework
- Griffen et al.: matched molecular pairs as a medicinal chemistry toolCited method; matched molecular pair definitions
Technical questions
What is a Matched Molecular Pair (MMP) in medicinal chemistry?
A matched molecular pair consists of two molecules that share an identical core structure and differ by only a single, well-defined structural transformation at one attachment point, such as replacing a C–H bond with a C–F bond, a methyl group, a methoxy group or a ring nitrogen.
Why calculate ΔLLE (ΔpIC50 − ΔcLogP) when evaluating a substituent change?
Adding a hydrophobic group such as a chlorine atom or trifluoromethyl group often improves biochemical potency (pIC50) simply by increasing non-specific hydrophobic partitioning (cLogP) by 0.6 to 0.9 units. Checking whether ΔpIC50 exceeds ΔcLogP distinguishes genuine pocket complementarity from lipophilicity-driven potency inflation.
Why does replacing a phenyl CH with a pyridine nitrogen lower cLogP and increase TPSA?
Replacing an aromatic CH group with an sp² ring nitrogen (an aza-scan edit) removes a hydrophobic carbon contribution and introduces a lone-pair hydrogen-bond acceptor. In an independent RDKit check the edit adds 12.89 Ų to TPSA and lowers Crippen logP by 0.605 units in each of the four contexts tested (benzene to pyridine, toluene to 4-methylpyridine, acetanilide to 4-acetamidopyridine and benzamide to isonicotinamide). The Crippen method is additive over atom types, so a substitution pattern that changes the types of the atoms next to the new nitrogen can give a different shift.
Connected workflows
- Structural edits and property comparison
Compare single-substituent MMP shifts with functional-group bioisostere edits.
- TPSA and Crippen logP calculation
Review the Wildman–Crippen logP and Ertl TPSA fragment contribution methods.
- 4PL IC50 curve fitting
Pair calculated ΔcLogP values with experimental pIC50 shifts to evaluate LLE.