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End-to-end, physics-based solutions for macrocycle modeling
Schrödinger’s macrocycle modeling workflows bring physics-based accuracy and scalable automation to macrocycle design, conformational sampling, docking, and optimization all on a single platform.
Modeling built for macrocycles, not adapted to them
0.40Å
median backbone RMSD for macrocycle sampling accuracy
65% → 88%
docking success rate
1.06
kcal/mol RMSE across diverse macrocycle systems
Schrödinger’s end-to-end macrocycle pipeline
Explore macrocyclic ligands, cyclic peptides, and constrained analogs with greater confidence.
Ideation
Convert a linear lead into a macrocycle automatically.
Automated macrocyclization workflow that enumerates common linker chemistry between user- or auto-defined attachment points
Built-in linker and protein sidechain libraries or bring your own
Physics-based scoring to identify the best candidates
Conformational sampling
Overcome the natural kinetic barriers that limit other sampling methods.
Prime macrocycle sampling (Prime-MCS) is an efficient sampler for generating accurate conformational ensembles for diverse macrocyclic compounds apriori
MacroModel for robust exploration of local macrocycle conformational space
Replica exchange with solute tempering (REST) molecular dynamics simulations extend sampling to large, flexible cyclic peptides
Desmond for metadynamics simulations to predict macrocycle stability
Binding pose prediction
Purpose-built docking technologies for large, flexible rings – not a small molecule workflow stretched to fit.
Glide with specialized macrocycle ring sampling enables large scale virtual screening
MacroDock is a purpose-built solution for high-accuracy macrocycle docking that combines dedicated macrocycle sampling technologies with Glide docking
Peptide workflow (TBD) for docking of large, flexible cyclic peptides in a fold and dock approach
Binding affinity prediction
The same rigorous FEP+ engine trusted for small molecules, now validated for macrocyclic and peptidic series.
Dedicated solutions for ligand alignment and system preparation of congeneric macrocycle series for FEP+
FEP+ accurately predicts affinities for linear-to-macrocycle transitions and other ring closing transformations
Integrated replica exchange with solute tempering (REST) for sampling across conformational energy barriers in FEP+
Support for custom torsion parameters for novel macrocycle chemistry
Strong retrospective performance across multiple published peptidic and non-peptidic macrocycle series
Permeability prediction
Screen for oral bioavailability before you ever synthesize a ring.
Prime-RRCK enables high-throughput modeling of experimental macrocycle RRCK permeability data
Cyclic peptide passive permeability and active transport classification
Why macrocycles require specialized modeling
Macrocycles occupy a unique chemical space between small molecules and biologics that often breaks assumptions built into common small molecule modeling software. Their constrained ring systems can improve potency, selectivity, and target engagement, but they also introduce unique modeling challenges:
Large, flexible rings can adopt many low-energy conformations
Bioactive conformations may be difficult to sample with standard methods
Ring closure strategies can strongly affect stability and binding
Docking requires accurate treatment of both ligand flexibility and receptor interactions
Permeability and developability often depend on subtle conformational effects
Publications
Life Science Publication
Accurate physics-based flexible docking of macrocyclic ligands
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