Small Molecule Drug Discovery

Platform Environment

Maestro Graphical Interface

• New Welcome Screen on startup provides quick access to common tasks such as creating and opening projects and importing structures
• Modernized and streamlined Project Table for enhanced usability
  • New Table Configuration pane allows fast switching between Light and Dark themes and toggles visibility of the ePlayer and Property Tree.
  • New Gadgets Menu provides convenient access to Charts and the 2D Viewer
• New Workflow Action Menu (WAM) to view spectroscopy results from Jaguar and Jaguar Spectroscopy calculations in the Project Table

Target Validation & Structure Enablement

Protein Preparation

• Improved minimization protocol to support broader coverage of biological and chemical systems
• Produce more reliable prepared structures by expanded coverage of equivalent tautomeric ligand states
• More easily view serious structural issues by filtering diagnostic reports with a severity threshold
• New ‘Missing Atom’ tab on the Diagnostics panel enables select sidechain and loop modeling

Cryo-EM Model Refinement

• GlideEM poses are now sorted by GlideScore which is more discriminating in ranking low RMSD structures than Denscore

Ligand Preparation

Ligand Docking

• Faster Glide scoring and docking with optimized Glide (Beta): Screen larger libraries and find better candidates with optimized Glide, including enhanced Active Learning Glide and Python API support
  • Same industry-leading Glide docking funnel and scoring functions, Emodel and GlideScore
  • Faster turnaround with same compute resources for Active Learning Glide and AutoDesigner
  • Advanced Python API support offers easy automation and file control over docking process for greater experimentation
  • Accessible through the new Ligand Docking panel that enables setup of Active Learning and Glide calculations

ABFEP

• Energy Decomposition data is now reported in Analysis PDF reports

Lead Optimization

FEP+

• New FEP+ Pose Builder workflow for automatically generating high-quality ligand alignments (Beta): Generate FEP-ready poses faster and run FEP+ at scale with an automated workflow designed for unbiased selection and robust atom-mapping
• Ability to read and write FEP+ Protocol files directly in the FEP+ Panel
• Improved Classification matrix styling
• Kendall’s tau statistic added to the statistical metrics reported
• Improvements to exported FEP+ data in csv/xls formats
• Added ‘None’ as a new Hot Atom Rule

Protein FEP

• FEP+ Residue Scan supported in Protein FEP+ for Ligand Selectivity panel

Constant pH Simulations

• Added support for Cysteine residues

FEP+ Protocol Builder

• Sharply reduced compute resources to run default workflow by shrinking initial simulation times to 0.5 ns and extended times to 10 ns
• Seamless interconnection as FEP+ Panel can now Read/Write Protocol Builder files
• Bias the selection of protocols to extend including compute efficiency via Pareto analysis (command line only)
• Added support for covalently bound ligands
• Ability to optionally sample charge states of GLU, ASP, LYS, ARG, and CYS in protocol optimization

De Novo Design

AutoDesigner – R-group Design

• New R-group Similarity score feature to focus ideation around compounds of interest
• New Design Rationale capability to improve ADME endpoints with respect to reference ligands

Alternative Modalities

Bifunctional Degraders

• Expanded support for protein degrader modeling with the new Degrader Sampling Workflow (Beta): Generate accurate degrader ternary complexes through integration of protein-protein docking and linker sampling in a structure-based workflow

Biologics Drug Discovery

• Augmented AI/ML capabilities for biologics with machine learning-based T-Cell Receptor (TCR) structure prediction (Beta): Perform high throughput structure prediction and large scale modeling of TCRs with the ImmuneBuilder deep learning model and Prime
• New Macromolecular Pose Filtering panel to filter native or near native poses from an ensemble of complexes using experimental data such as HDX-MS

Materials Science

GUI for Quantum ESPRESSO

Product: Quantum ESPRESSO (QE) Interface

• A new environment variable for the location of Quantum ESPRESSO binary

Transport Calculations via MD simulations

Product: MS Transport

• Thin Plane Shear: Selection of slab region by molecular units

KMC Charge Mobility

Product: MS Mobility

• Compute KMC Charge Mobility: Predictions based on Schrödinger’s new mobility engine

Materials Informatics

Product: MS Informatics

• Machine Learning Property: Updates to existing models
• Machine Learning Property: Prediction of triplet reorganization energy
• Machine Learning Property: Prediction of S1-to-T1 energy gap (∆EST)
• Machine Learning Property: Predictions from the interactive mode automatically added to the Project Table
• MLFF Calculations (Beta): Single-point energy and geometry optimization tool using Schrödinger’s latest machine-learned force fields

Formulation ML

Product: MS Formulation ML

• Formulation ML: Support for custom ingredient descriptors
• Formulation ML: Support for creating models using multiple CPUs in parallel
• Formulation ML: Support for setting mixtures as individual components
• Formulation ML Optimization: Workflow solution to optimize materials formulations

Layered Device ML

Product: MS Layered Device ML

• OLED Device ML: Workflow solution to predict OLED device performance
• Optoelectronic Device Designer: Use ML OLED device models to predict performance

Coarse-Grained (CG) Molecular Dynamics

Product: MS CG

• Automated CG Mapping: (+AUTOMAPPING_MARTINI_PROTEIN) Support for proteins in automated mapping and parameterization for Martini
• Automated CG Mapping: Accurate mapping for carbohydrate systems
• Improved threshold for momentum errors in CGMD simulations
• CG FF Builder: Parameters for water-water interactions fixed by default

Dielectric properties

Product: MS Dielectric

• Complex Permittivity: Option to run replicates in parallel

Reactivity

Product: MS Reactivity

• Reaction Network category created under the Materials task menu
• Reaction Workflow renamed to Reaction Network Profiler
• Auto Reaction Workflow renamed to Reaction Network Enumeration Profiler
• Reaction Network Profiler: Option to run conformational search using CREST
• Reaction Network Profiler: Conformational search included in restarts (command line)
• Nanoreactor: Option to screen products by energy relative to reactant state
• Nanoreactor: (+ELEMENTARY_REACTION_NETWORK) Support for the Elementary Reaction Network workflow

Microkinetics

Product: MS Microkinetics

• Microkinetics Deposition Analysis: Workflow solution to run post-analysis of microkinetic simulations in deposition or etch processes of solid materials
• Microkinetic Modeling: (+MATSCI_MKM_INTERACTIONS) Support for simple quadratic adsorbate-adsorbate interactions

Reactive Interface Simulator

Product: MS RIS

• Solid Electrolyte Interphase: Option to block intramolecular reactions (command line)
• Solid Electrolyte Interphase: Option to use DFT charges for new species

Crystal Structure Prediction

Product: Crystal Structure Prediction

• Crystal Structure Prediction: Interface and workflow to predict crystal structures and polymorphs for a given molecular compound

MS Surface

Product: MS SurfChem

• Adsorption Enumeration: Access to workflow assessing reactive adsorption
• Desorption Enumeration: Workflow solution for assessing desorption of multiple molecules

MS Maestro User Interface

• Direct link from the task menus to Materials Science Panel Explorer page

MS Maestro Builders and Tools

• Structured Liquid: Automatic standardization of custom lipids
• Polymer: Improved dihedral setups for multiple shortest-length backbones
• Organometallic Conformational Search: Option to run conformational search using CREST

Classical Mechanics

• Evaporation: Option to export the results as CSV file
• MD Multistage: Center of mass motion removed for coarse-grained systems
• Thermophysical Properties: Option to save trajectory energy file
• Umbrella Sampling (Beta): Workflow solution for umbrella sampling of membranes

Quantum Mechanics

• Adsorption Energy: Support for reactive adsorption and desorption energies
• Adsorption Energy: Improved assessment of entropy loss during the adsorption
• Bond and Ligand Dissociation: Option to set product charges from formal atomic charges
• Bond and Ligand Dissociation: Support for PCM and SMD solvent models
• Bond and Ligand Dissociation: Improved 2D visualization of charges and radicals in product fragments
• Crest: UI for semiempirical QM based conformational search using CREST
• Optoelectronic Film Properties: Support for multiple reorganization energies as input for computing intersystem crossing (ISC) rate
• Optoelectronic Film Properties Viewer: Support for user-input reorganization energies to instantly re-evaluate SEET rate
• Thermochemistry Viewer: Support for viewing reactive adsorption and desorption energies
• Trajectory Density Analysis: Improved naming scheme for atom groups

Education Content

Life Science

• New tutorial: Exploring Protein Binding Sites with Mixed-Solvent Molecular Dynamics
• New tutorial: Introduction to T-Cell Receptor Modeling with BioLuminate
• Updated tutorial: Antibody Visualization and Modeling in BioLuminate
• Updated tutorial: Peptide Modeling with BioLuminate
• Updated tutorial: Target Analysis with SiteMap and WaterMap
• New QRS: Structure Reliability Report
• New QRS: Custom Reactions for Covalent Docking
• New QRS: Mixed-Solvent Molecular Dynamics
• Updated QRS: GlideWS Model Generation
• Updated QRS: MM-GBSA Residue Scanning

Materials Science

• New Tutorial: Umbrella Sampling
• New Tutorial: Crystal Structure Prediction
• New Tutorial: Optimization of Formulations Using Machine Learning
• New Tutorial: Machine Learning for OLED Device Design
• New Tutorial: Nanoemulsions with Automated DPD Parameterization
• New Tutorial: Applied Machine Learning for Formulations
• Updated Tutorial: Atomic Layer Deposition
• Updated Tutorial: Design of Asymmetric Catalysts with Reaction Network Enumeration Profiler (previously AutoRXNWF)
• Updated Tutorial: Machine Learning Property Prediction
• New QRS: CREST
• New QRS: Microkinetics Deposition Analysis

LiveDesign

What’s Upcoming in 2025-2

• Enhanced support for antibody-drug conjugates: Import ADCs from a source database and view the entire subcomponent hierarchy in the spreadsheet
• Improved collaboration with freeform column comments: View a comment thread in the main spreadsheet and enable a structured, context-specific conversation with user attribution and timestamps
• Ability to standardize workflows with form templates: Create a standardized data view or analysis, and add the Form to other LiveReports
• New and updated protocols: The FEP+ Pose Builder Protocol has been updated and a new FEP+ Amenability Protocol returns additional pose quality metrics.

Small Molecule Drug Discovery

Target Validation & Structure Enablement

Protein Preparation

• Improved peptide bond connectivity by better integration of sequence information in the Protein Preparation Workflow (PPW)

Protein X-Ray Refinement

• Phenix/OPLS can now run from CIF files containing reflections

Cryo-EM Model Refinement

• Improved support of macrocycles in GlideEM/GlideXtal

Binding Site & Structure Analysis

Binding Site Characterization

• Rationalize kinase selectivity challenges using the Kinase Conservation Analysis Interface that combines sequence and complex structural information: Identify promising selectivity handle residues to modulate ligand kinase selectivity that can be tested with FEP+ Residue Scan

Desmond Molecular Dynamics

• Optimize the unbinding kinetics of protein-ligand complexes using dissolution rate predictions based on unbinding pathways identified by enhanced sampling methods

Mixed Solvent MD (MxMD)

• Identify potential binding sites and assess drugability of competitive and allosteric binding sites with the full release of a Mixed Solvent Molecular Dynamics Interface to setup and analyze MxMD simulations

Hit Identification & Virtual Screening

Active Learning Applications

• Improved diversity of top scoring ligands in Active Learning ABFEP by using 3D features extracted from Glide poses in ML model building
• Researchers can now specify different batch sizes and selection rules to exploit or explore for each iteration in Active Learning simulations

Lead Optimization

Protein FEP

• View trajectories and structural output from FEP+ Residue Scans in the FEP+ interface
• Rationalize key interactions in ligand binding using per-contact residue interaction energy analysis which is new for ABFEP
• Easily identify disconnected sub-maps in a busy FEP map

Spectroscopy

• More accurate NMR spectra predictions by identifying magnetically inequivalent nuclei

Macrocycles

• Automatically enumerate and cyclize peptide sequences from FASTA files with the new cyclize_peptide.py script
• Ring template generation for Glide macrocycle docking with bespoke parameters is now automated by the macrocycle_template_gen.py script
• An updated macrocycle_sample.py script with greater control of sampling options and a new receptor-aware macrocycle sampling algorithm that includes surrounding receptor atoms to restrict conformational search space
  • Updated macrocycle_sample.py script replaces macro_sample.py
• Improved handling of ring nitrogen atom substituents during ring template conformation generation
• tug_align.py now supports 2D ligand files as inputs
• tug_align.py exposes several new command-line options that allow finer control of the alignment convergence criteria which are useful in reducing convergence times for large molecules such as cyclic peptides

Medical Chemistry Design

Ligand Designer

• Enable user-specificed or automatically generated ligand protonation and tautomeric states from the 2D/3D editing workflow for MCS Docking

Biologics Drug Discovery

• Completely rewritten MMGBSA Residue Scanning backend that is more reliable and has improved support for a wider variety of non-standard amino acids and mutation of DNA/RNA
• New high-throughput, machine learning-based antibody and nanobody structure prediction with ImmuneBuilder. With throughput of about one minute per structure, it is suitable for batch modeling of thousands of structures
• Automatically identify and annotate for visualization TCR alpha and beta chains from a FASTA file (commandline run_tcr_modeling.py)
• Updated N-glycosylation PROSITE pattern that is less restrictive

Materials Science

GUI for Quantum ESPRESSO

Product: Quantum ESPRESSO (QE) Interface

• Workflow solution to calculate the defect energy
• Workflow action menu (WAM) for output from periodic DFT convergence test
• Support for setting total magnetization/charge for each structure
• Support for computing thermodynamic properties via dynmat.x (command line)
• Support for stopping an NEB calculation and returning intermediate structures

Materials Informatics

Product: MS Informatics

• Formulation ML: Option to control advanced settings
• Machine Learning Property: Skip structures outside the model scope
• Machine Learning Property: Prediction of singlet (S0) to triplet (T1) energy
• Machine Learning Property: Prediction of hole / electron reorganization energy
• Machine Learning Property: Prediction of orbital (HOMO / LUMO) energy
• Machine Learning Property: Updates to existing models

Coarse-Grained (CG) Molecular Dynamics

Product: MS CG

• Automated CG Mapping: Mapping MARTINI for speciality chemicals / polymers
• CG FF Builder: Support for exporting atomistic reference data

Dielectric properties

Product: MS Dielectric

• Complex Permittivity: Linear fitting parameter retained during exponential fitting

Reactivity

Product: MS Reactivity

• Nanoreactor: Control over thermostat bath temperature
• Nanoreactor: Support for parallelization of xTB dynamics simulations
• Reaction Workflow: Support for the use of the xTB Hessian for transition states
• Reaction Workflow: Use of input conformers when conformation search fails
• Reaction Workflow: Improved SCF convergence for energy calculations

Microkinetics

Product: MS Microkinetics

• Microkinetic Modeling: Improved speed/scalability by up to 2 orders of magnitude
• Microkinetic Modeling: Improved model for multiple catalysts / catalyst site types
• Microkinetic Modeling: Improved data visualization in the viewer
• Microkinetic Modeling: Job name shown in the viewer

Reactive Interface Simulator

Product: MS RIS

• Solid Electrolyte Interphase: Improved subjob queuing coordination
• Solid Electrolyte Interphase: Support for constant pressure (NpT) simulations (command-line)

MS Maestro Builders and Tools

• GUI panel to digitally design, manage, and visualize OLED devices
• Single Complex: Improved UI for better usability
• Solvate System: Support for generating multiple configurations by random seeds

Classical Mechanics

• Workflow solution to compute thin plane shear friction
• Barrier Potential for MD: Support for reading barrier information from entry
• Evaporation: Option to plot total number of molecules removed from the system
• Evaporation: Information tied to barriers (when applied) logged in the output
• Polymer Crosslink: Improved speed by efficient checking for ring spears
• Trajectory Density Analysis: Option to display multiple density depths
• Trajectory Density Analysis: Export option for 2D heat-map plot

Quantum Mechanics

• Workflow solution to plot phase diagrams based on energy
• Workflow solution to compute and analyze computational ellipsometry data
• QM Convergence Monitor: Easy access to the structure from the last step

Education Content

Life Science

• New tutorial: Refining crystallographic protein-ligand structures using GlideXtal and Phenix/OPLS

Materials Science

• New tutorial: Automated Martini Fitting for Coarse-Grained Simulations
• New tutorial: Thin Shear
• New tutorial: Defect Energy Calculation
• New tutorial: Optoelectronics Device Designer
• New tutorial: Computational Ellipsometry
• New tutorial: Phase Diagrams
• New tutorial: Ab initio Molecular Dynamics Simulations of Li-ion Diffusion in Solid State Electrolytes
• Updated tutorial: Microkinetic Modeling
• Updated tutorial: Organometallic Complexes

LiveDesign

What’s New in 2025-1

• Biologics
  • Forms view now require the Sequence Viewer to drilldown from another widget
  • Performing a sequence alignment now shows an alert indicating the type of Alignment, and provides a “Try Again” button if the alignment fails
  • Forms views that contain both a Sequence Viewer and 3D Visualizer permit a synchronized selection of amino acid residues, such that selecting an amino acid in the Sequence Viewer will highlight the amino acid in the 3D Visualizer, and vice versa
  • Sequence search options now permit searching the Database, Active LiveReports, and Other LiveReports
  • View non-natural amino acid molecular structure in a tooltip by hovering over residues in the sequence viewer
  • Toggle monomers’ display format in the sequence viewer to view either single-letter FASTA format, or a custom symbol for non-natural monomers (up to 6 characters)
  • Reset Gap Penalties, Numbering Scheme, and Scoring Metrics to their default values for each alignment method
  • Substructures searches in Advanced search panel support a “Match by Child” option, which enables searching against an entity’s subcomponents
• Performance Improvements
  • Small Molecules uploaded from file imports, enumeration, and Maestro uploads appear in the LiveReport more quickly
• Landing Page: View all of a compound’s experimental data on the Compound’s detail page
• Data and Columns Tree:
  • Group Multi-Parameter Optimization columns and Formulas columns into folders
  • The button text to create new Formulas, MPOs and FFCs has been changed from “NEW” to “CREATE”
  • Published Limited Assay Columns now show the [LIM] prefix in the Data & Columns Tree
• A new MAE-FILE macro for Protocols in the Admin Panel allows Protocol and Models to access compounds and biologics using a Maestro file format. The Maestro file format includes residue information for Biologics
• Configure LiveDesign to send an email on usage statistics, including: the number of unique logins over the last month, total number of active users, Number of compounds added last week, total number of compounds, total number of LiveReports updated last week, total number of active LiveReports and number of active LiveReports. For each user, the following information is reported: username, date of first login, date of last login, number of owned LiveReports
• Configure a server-wide search setting to set the default searching behavior in the search panel to the Database, the Active LiveReport, or Other LiveReports
• A new LDClient method, get_all_compounds(), enables retrieving all compounds within a specified list of projects
• Sketched reactions within the Reaction Enumeration tool can now use atom queries to add greater specificity to the reaction definition

What’s Been Fixed

• Previously, changes to gap penalties were not persisting when saved in the Forms view, and now gap penalty values will persist correctly upon modification and saving
• The “Batch Create Limited Assay Columns” option previously was unavailable in the column menu, if the column was within a column group, and now the option always appears
• The residue synchronization between the 3D Visualizer and Sequence Viewer now remains functional even after changing the numbering scheme in Sequence Viewer
• Model results would occasionally appear as Failed in the LiveReport, when in fact the model ran successfully, and now model results correctly show results in the LiveReport
• The Assay Viewer Tool would occasionally change the date filter to 0 days and would not show data, and now defaults to showing data that was uploaded within the previous day.
• Model results would occasionally appear as Failed in the LiveReport, when in fact the model ran successfully, and now model results correctly show results in the LiveReport
• Ligand Designer’s deleted poses would occasionally reappear, and now no longer reappear
• Protocols and Models showed their created date as one day earlier than their actual created date, and now show the correct date
• LiveReport filters did not support filtering for Real or Virtual Biologics, and now provide quick toggles to apply those filters
• Opening a model attachment from the main spreadsheet (e.g., a LID from a Glide model) would fail to show the image, and now correctly shows the image
• Plot tooltips could not be dragged and moved after pinning to the screen, and now can be dragged to a new position after pinning
• Importing a biologic entity would occasionally not show its subcomponents in the main spreadsheet, and now will correctly show its subcomponents
• LiveDesign would occasionally fail to open LiveReports due to a database lock, and now no longer will freeze
• Filtering out a frozen row would show flashing squares in the first row in the main spreadsheet, and now correctly shows that row’s data
• The sequence viewer would show all entities in the LiveReport, even when only one entity was selected, and now correctly shows only the selected entities
• Horizontally scrolling the sequence viewer would reset the ruler, and show the wrong residue numbers at the top, and now shows the correct residue numbers
• Opening the Project Picker would occasionally take several seconds to show the list of projects, and now shows the list of projects immediately
• LiveDesign would occasionally fail to open LiveReports due to a database lock, and now no longer will freeze
• Filtering out a frozen row would show flashing squares in the first row in the main spreadsheet, and now correctly shows that row’s data
• Exporting a LiveReport defaulted to exporting a subset of columns, and now defaults to exporting all of the columns
• Syncing LiveDesign users with external authentication systems would fail because LiveDesign counted unlicensed users against the total license count, and now permits syncing users as long as there are available licenses
• License files would occasionally fail to upload in the Admin Panel UI, and now correctly upload
• User email addresses would not save in LiveDesign when using Single Sign-on, and LiveReport notifications would not be emailed to users. Email addresses and are now correctly saved
• LiveReport tabs would disappear after logging out and logging in, and now correctly appear after logging back in
• Duplicating a LiveReport defaulted to copying a subset of columns, and now defaults to copying all of the columns