Activity Data Mining / SAR / Matched Molecular Pairs / R-group Analysis / R-group Profiling / Free-Wilson Analysis / Compound Suggestions

Matched Molecular Pair analysis on an activity data set enables finding activity cliffs and bioisosteres, providing insight on parts of a molecule that must remain fixed or which can be varied to advance a campaign. If activity against multiple related targets is present, selectivity information can also be gleaned. Analyzing and profiling the functional groups present in a data set can point up useful routes to improving properties such as those relevant for DMPK. This webinar will demonstrate MOEsaic, which enables these analyses in a browser interface which is easy to use and interpret, and which takes analysis one step further by suggesting potential new compounds, not present in the original data sets, which are most likely to display desirable activity and property profiles.

Molecular Surfaces and Maps / Ligand Interactions / Docking / Ligand Optimization / Ligand Selectivity / Protein Alignments and Superposition

The course covers MOE applications for interactive structure based design. Examples include active site visualization, protein-ligand contact analysis and ligand modification/optimization in the receptor pocket. Use of the docking module and its application to assess ligand flexibility will be discussed. A protocol for aligning and superposing protein complexes in the context of protein selectivity will be studied.

Molecular Fingerprints / Pharmacophore Elucidation / 3D Query Generation / Ligand-Based Drug Design / Virtual Pocket, vHTS

Incorporating 3D information into small-molecule drug design can be challenging when structural data for the biological target is absent. Given a series of ligands and associated activity data, we show how reverse fingerprints can identify mportant molecular motifs and generate a consensus pharmacophore query that includes atom-centered and projected features. Ligand shape and excluded volumes features can be derived from the ligand ensemble, and physical properties such as charge and lipophilicity can be mapped from the ligand ensemble onto the ligand shape surface and onto a "pocket surface" created at the ligand shape/excluded volume interface. The resulting "virtual pocket" is a hypothesis of how the ligands appear in the bound state, and what the binding pocket looks like around the bound ligands. The virtual pocket can be used for retrospective analysis or converted to a 3D pharmacophore query that can be used to search databases for new active molecules in a vHTS context.

Protein Alignments and Superposition / Loop and Linker Modeling / Homology Modeling / Protein- Protein Docking / Protein Solubility Analysis / 2D Hot Spot Mapping / PLIF / Biologics QSAR Modeling

The course covers methods for aligning protein sequences, superposing structures, homology modeling fusion proteins and conducting protein-protein docking. In particular, an approach for aligning and superposing multiple structures will be described for determining structural and surface protein variations in relation to protein property modulation. A method for grafting and refining antibody CDR loops as well as using a knowledge-based approach to scFv fusion protein modeling using the MOE linker application will be described. An approach to generate homology models of a murine antigen structure from a human template as well as protein-protein docking of an antibody to an antigen will be discussed. A QSAR model for predicting and analyzing protein/biologics solubility will be described.

Protein Engineering / Protein Properties / Developability / Hot Spot Analysis / Antibody Modeling / Humanization / Molecular Surfaces

The course covers approaches for structure-based antibody design and includes protein-protein interactions analysis, in silico protein engineering, affinity modeling and antibody homology modeling. The interaction of a co-crystallized antibody-antigen complex will be studied by generating and examining the molecular surfaces and visualizing protein-protein interactions in 3D and 2D. Antibody properties will be evaluated using specialized calculated protein property descriptors and analyzing protein patches. The application of protein engineering tools for homology modeling and conducting property optimization of antibodies in the context of developability will be studied. Antibody optimization examples will include identification of glycosylation sites and analysis of correlated pairs using a specialized antibody database. An approach for humanizing antibody homology models will be discussed. All the steps necessary for producing and assessing antibody homology models will be described.

Structure Preparation / Protein Binding Site Visualization / Template-Based Docking / Covalent Docking / Pharmacophores / Protein-Ligand Interaction Fingerprints (PLIF) / Multiple Processor Calculations

Advanced docking workflows encountered in drug discovery projects will be described, which include a range of related topics from the application of pharmacophore constraints in docking to the analysis of protein-ligand interaction fingerprints (PLIF) generated from docked poses. Examples include: (1) general docking with applied pharmacophore constraints, (2) template-based docking using a scaffold or fragment to guide placement, and (3) covalent docking to generate, rank and score ligands that are covalently bound to a protein/receptor. Leveraging multiple processing capacity will also be presented.

Structure Preparation / Force Field / Solvation / AMBER / NAMD / Visualization / Player

Setting up a Molecular Dynamics simulation starting from a protein PDB structure can be challenging. It involves: data preparation, force field parameterization, running protocols and trajectory analysis/visualization. MOE provides a streamlined interface which allows for easy setup, execution and visualization of MD trajectories via AMBER, NAMD or the internal MD engine. In this webinar, the complete workflow to run MD simulations will be introduced.

Conformational Search / Molecular Dynamics / Macrocycles / Loop Modeling

We present a method for conformational search of complex molecular systems such as macrocycles and protein loops. The method is based on perturbing an existing conformation along a molecular dynamics trajectory using initial atomic velocities with kinetic energy concentrated on the low-frequency vibrational modes, followed by energy minimization. A novel Chebyshev polynomial filter is used to heavily dampen the high-frequency components of a randomly generated Maxwell−Boltzmann velocity vector. The method is very efficient, even for large systems; it is straightforward to implement and requires only standard force-field energy and gradient evaluations. The results of several computational experiments suggest that the method is capable of efficiently sampling low-strain energy conformations of complex systems with nontrivial nonbonded interaction networks.

Protein Engineering / Protein Properties / Developability / Hot Spot Analysis

The workshop covers approaches for structure-based antibody design and includes protein-protein interactions analysis, in silico protein engineering, affinity modeling and antibody homology modeling. The interaction of a co-crystallized antibody-antigen complex will be studied by generating and examining the molecular surfaces and visualizing protein-protein interactions in 3D and 2D. Antibody properties will be evaluated using specialized calculated protein property descriptors and analyzing protein patches.

Docking / Pharmacophore Modeling / Fragment-Based Design / Scaffold Replacement / Protein-Ligand Interaction Fingerprints (PLIF)

This workshop will cover some advanced workflows for structure-based design in drug discovery projects. The application of pharmacophores in the context of protein-ligand docking and scaffold replacement will be included, as will the generation and analysis of protein-ligand interaction fingerprints (PLIF). Participants will therefore experience a broad range of computational tools that can be brought to bear for lead generation and optimization.

Molecular Databases, Conformational Searching, Small-Molecule Superpositions / Flexible Alignment / Pharmacophore Modeling and Searching / Molecular Fingerprints

The course will cover some essential in silico methods needed for guiding drug discovery projects in the absence of a protein structure. Molecular alignments and conformational analyses of molecules from a congeneric series will be used to investigate the impact of ligand substituents. A pharmacophore model will be created based on a pair of superposed ligand structures, and then used to identify new compounds matching the required pharmacophore features. Other topics covered will include fingerprint-based similarity searching and manipulation of MOE databases.

Structure preparation / Non-natural amino acids / Conformational searching / Distance restraints / Peptide-protein docking / Protein-ligand interaction fingerprints

The course covers methods for analyzing and optimizing peptide-protein interactions in the active site. Topics related to peptide-protein structure preparation, peptide sequence optimization using natural and non-natural acids and conformational analysis will be discussed. Peptide-protein docking and protein-ligand interactions to analyze contact points will be described. The course will also cover advanced conformational searching using distance restraints.

Protein Annotation / Protein Patches / Virtual Mutagenesis / Antibody Homology Modeling / Protein Properties / Developability

The workshop covers the application of computational tools for modeling the structures of antibodies, for humanization, and for optimization of properties to enhance developability. Examples will include the identification of glycosylation sites and analysis of correlated pairs using a specialized antibody database. The calculation of protein properties and their optimization to facilitate developability as a product will also be covered.

MOE Databases / Descriptors / Fingerprints / QSPR Modeling / Pharmacophore Modeling / Template-Forced Docking / Scaffold Replacement / MedChem Transformations

The course covers the suite of MOE applications which can be applied to small-molecule virtual screening. Topics include the preparation of small molecule databases for virtual screening, filtering databases based on substructure matching and property values, building QSAR/QSPR models and fingerprint similarity models as database filters, pharmacophore query creation and searching, and small-molecule docking. These tools are used in conjunction to present a complete virtual screening workflow. The creation of de novo structures using the MOE Scaffold Replacement and MOE Medchem transformation applications is also covered.

Mixed methods / Quantum Mechanics / Molecular Mechanics / Gaussian / ONIOM

Detailed understanding of electronic effects are critical for properly understanding enzymatic reactions, or processes that occur in solution (as just two examples). However, it remains impractical to apply quantum mechanical (QM) approaches to such large biological systems. As a compromise between computational cost and predictive accuracy, mixed method approaches allow us to rigorously partition a system into regions that are treated classically (using molecular mechanics) and (typically) smaller regions that are treated using QM. This partitioning scheme allows the user to focus the more realistic electronic treatment to where it is most needed, providing the practical balance of accuracy and timeliness. The ONIOM scheme, as implemented in the Gaussian electronic structure package, allows for the partitioning of a system into multiple regions, each of which can employ a different level of theory. In MOE 2020 we have created a simple and intuitive interface to set up ONIOM calculations. Using MOE’s powerful ‘selection language’, the assignment of layers is trivial, as is the creation of all required Gaussian input files. These calculations can leverage the new high-performance compute framework available in MOE 2020 to seamlessly be executed, either locally or remotely, using MOE as a simple front-end to your computational queuing system. During this webinar we will provide a brief theoretical orientation to the ONIOM method, followed by a demonstration of how to set up, execute, and analyze ONIOM calculations directly from within the MOE platform.

Protein-Protein Docking / Molecular Surfaces / Protein Patches / Interaction Fingerprints / Clustering / Epitope Analysis

The MOE Protein docking application is used to map epitopes and other protein-protein interfaces (PPI). This automatically calculates a PPI fingerprint for each pose. The poses are clustered using the fingerprint, and epitope residues are identified from the top ranking clusters. The poses can then be annotated in the MOE Window, for browsing through all the top epitopes.

Macromolecular repository / 3D query searching / Pocket similarity / Display electron density / Central repository / Specialized protein databases

PSILO® is a web-based platform for the deposition and analysis of macromolecular structural information. The workshop will describe the application of PSILO® for mining biomolecular data. Approaches to query generation and search result navigation in PSILO will be covered in detail; for example, 3D contact searching, and protein pocket similarity searching. The PSILO and MOE platforms are tightly integrated, and the ability to perform PSILO search queries directly from within MOE will also be described.

Structure Preparation / Sidechain Rotamer Exploration / Electron Density Maps / X-Ray / CryoEM / Solvent Analysis with 3D-RISM

The course will cover methods for evaluating, analyzing and refining protein models derived from electron density data. Topics related to protein structure preparation and side-chain conformational analysis and placement will be discussed. Visualization and interpretation of electron density maps (X-ray/CryoEM) for assessing protein models will be described. The 3D-RISM method for predicting and refining the placement of solvent molecules in protein models will also be presented.

Solvent Analysis / 3D-RISM / Lead Optimization / Water Placement

The investigation of water molecule placements, both real and potential, around a protein-ligand complex can provide possible routes for enhancing ligand affinity. For example, calculations using the 3D-RISM method on a crystallographically determined complex enable the identification of water molecules whose displacement by a modified ligand may enhance binding. The theory behind the method, its application and validation will be presented.

Scaffold Replacement / Fragment Linking / R-Group Screening / Medicinal Chemistry Transformations / Fragment Libraries / Pharmacophore Models

Fragment-based drug design (FBDD) is a key approach in the discovery of high-quality drug candidates. As a complement to biophysical FBDD methods, in silico FBDD uses structure-based approaches to rapidly design and screen large libraries of virtual compounds, allowing for the exploration of a much larger chemical space. The webinar describes in silico FBDD methods ranging from scaffold-hopping to fragment linking and growing in the receptor active site. A method for generating a series of closely related derivatives through rule-based medicinal chemistry transformations is presented. The use of pharmacophore models and 2D/3D descriptors to guide in silico FBDD processes is also discussed.

Antibody Modeling / Antibody Properties / Developability / Protein Liability / HPC / Protein Family Databases

Improvements in structure and property predictions of proteins and antibodies continue in the new release of MOE. The IMGT scheme for antibody sequence annotation has been implemented, and the antibody modeler application has been enhanced in a number of ways, including its ability to use HPC resources. Conformational ensemble averaging in antibody structures is now used to calculate more accurate descriptors, which may be used to derive more robust models for protein liability and other developability-related properties for biological therapeutics. This webinar will cover these capabilities, along with introducing some new protein family databases.

Pharmacophore Modeling / Docking / Fragment-based Design / Scaffold Replacement / R-Group Screening / Project Search / Protein-Ligand Interaction Fingerprints

The course describes advanced SBDD workflows in drug discovery projects and encompasses a range of topics from pharmacophore query generation to protein-ligand interaction fingerprints. More specifically, the course will cover the application of pharmacophores in the context of protein-ligand docking, scaffold replacement and R-group screening. A method for querying a 3D project database will also be presented along with the generation and analysis of protein- ligand interaction fingerprints (PLIF).