Structure-Based Design

Macromolecular crystallographic data, when available, can be a valuable source of information for discovering active ligands. MOE provides a collection of applications for visualizing and understanding details of receptor active sites and receptor-ligand interactions. These applications are used to suggest improvements to ligands or screen ligand databases for candidate binders.

Active Site Detection Detect candidate protein-ligand and protein-protein binding sites using a fast geometric algorithm, based on Edelsbrunner’s alpha shapes. Each site on a macromolecular structure is ranked according to its accessible hydrophobic contact surface. Visualize individual sites or populate them with "dummy atoms" for docking calculations or starting points for de novo ligand design efforts.

Ligand:Protein Interaction Diagrams is an active site analysis tool to easily identify polar, hydrophobic, acidic and basic residues. Visualize solvent exposed ligand atoms and residues in close contact with ligand atoms as well as sidechain and backbone acceptor and donor interactions. Browse through a chemical series in 2D with fixed receptor and visualize conserved and unconserved interactions for selectivity analysis [Article]

Molecular Surfaces and Maps is an integrated application for active site analysis. Build Molecular Surfaces colored by properties, predict Contact Preferences using statistical knowledge-based potentials and calculate Electrostatic Maps using the non-linear Poisson-Boltzmann equation. Identify steric limits, regions for ligand modification and understand receptor recognition preferences. [Article]

Protonate3D Use Protonate3D to assign optimal free energy proton geometry and ionization states to macromolecular systems to improve the results of simulations, docking and active site analyses. Macromolecules, ligands, solvent and metals are assigned protonaton states using a Generalized Born electrostatics model. Tautomer, titration and conformation states are determined simultaneously using a sophisticated Unary Quadratic Optimization algorithm. [Article]

Ligand-Receptor Docking Dock small molecules in a macromolecular binding site. Supply a database of conformations or generate conformations on the fly based on potential energy models including solvation effects. Choose between various scoring functions and optionally constrain the generated poses to satisfy a pharmacophore query to bias the search towards known important interactions. Refine the poses using a forcefield based method with MM/GBVI scoring or a fast grid based method. An interface to FlexX is provided for high throughput virtual screening. The docking architecture is parallelized using the MOE/smp technology.

Multi-Fragment Search is an ensemble-based methodology for mapping the preferred locations of specific chemical groups in a receptor structure. An active site of a macromolecular structure is populated with a large number of chemical fragments, which are subjected to an energy minimization protocol. The resulting group locations are clustered, scored (including solvation effects) and output to a database for subsequent visualization and analysis.

LigX is a streamlined interface for interactive 3D ligand optimization in the active site. A dedicated button bar provides commands for structure preparation, active site analysis, molecular property/binding affinity calculations and ligand modification and optimization in the active site. LigX can be used by both computational and medicinal chemists.