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.

Scaffold Hopping / Fragment Linking / Ligand Growing / R-Group Screening / Medicinal Chemistry Transformations / Pharmacophores / Fragment Databases

The course will focus on fragment-based drug design tools in MOE. Combinatorial fragment design and scaffold replacement in the receptor active site will be covered in detail, along with approaches for fragment linking and growing. A method for generating a series of closely related derivatives through medicinal chemistry transformations will also be presented. Finally, the use of pharmacophores and 2D/3D descriptors to guide drug design processes will be discussed.

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.

Alignments and Superposition / Loop and Linker Modeling / Homology Modeling / Protein Docking / Solubility Analysis / 2D Hot Spot Mapping / Protein Ligand Interaction Fingerprints / QSAR Modeling

The course covers methods for aligning protein sequences, superpositioning structures, homology modeling fusion proteins and conducting protein-protein docking. In particular, an approach for aligning and superpositioning 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.

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

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).

Antibody Modeling / Developability / Aggregation / Viscosity / Clearance

In this work, we present a method for modeling antibodies and performing pH-dependent conformational sampling, which can enhance property calculations. Structure-based charge descriptors are evaluated for their predictive performance on recently published antibody pI, viscosity, and clearance data. From this, we devised four rules for therapeutic antibody profiling which address developability issues arising from hydrophobicity and charged-based solution behavior, PK, and the ability to enrich for those that are approved by the U.S. Food and Drug Administration. Differences in strategy for optimizing the solution behavior of human IgG1 antibodies versus the IgG2 and IgG4 isotypes and the impact of pH alterations in formulation are discussed.

Combinatorial Library Enumeration / Reaction Sketching / Reagent and Product Filtering / Simple and Multicomponent Reactions

MOE’s new Combinatorial Library Enumerator application is designed to help chemists select suitable reagents from available commercial or in-house libraries for use in reactions to explore potential or respond to already identified structure-activity and structure-property relationships, thereby finding new optimised compounds and potential synthetic routes to them. Based in a web browser, the application allows the user to select from a library of existing reactions or to sketch, optimize, “debug” and save their own using a streamlined, interactive interface. Sources of reagents may be entered and interactively filtered by chemistry or by a range of other properties. Simple or multicomponent reactions can be handled, and streamlined lists of identified reagents exported for purchase. The webinar illustrates these capabilities by looking for potential Poly (ADP-ribose) glycohydrolase (PARG) inhibitors - PARG is implicated in single-strand DNA repair and cell survival and so inhibition of PARG may lead to cancer therapies that aim to stop rapid proliferation of cancer cells.

Docking / Template Setup / Sketcher Integration / SMARTS Matches / Wildcards / SAR Analysis / Kinase Database Mining / Structure Preparation / Pharmacophores

A common strategy for optimizing the properties of a small-molecule lead compound is systematically vary the R-groups attached to the central scaffold of the lead compound. This can lead to a large number of analogues that would be time consuming to synthesize and test. Virtual docking can help narrow down the set of analogues by determining which can dock to the receptor pocket with the same binding mode as the lead compound and not incur significant clash with the receptor. Additional interactions with the receptor can also be detected. This webinar will focus on template-guided docking, a docking method which is particularly useful when probing the effects of R-groups on a set of analogues which exhibit the same binding mode. The webinar demonstrates the full template-guided docking workflow; determining common scaffolds of known binders, finding suitable receptor structures for docking, setting up the template-guided docking run and analyzing the docked poses for promising analogues.

Database Viewer / 2D, 3D, Carbohydrate and Sequence Displays / Plotting / Range and Rule-based Coloring / Images and Graphic Objects

This webinar focuses on the advanced visualization capabilities of the MOE Database Viewer. Topics include 2D and 3D molecule display options and carbohydrate depictions. The plotting functionalities will be discussed, which include energy profile and contour plots, histograms, correlation plots, and more. Dynamic color gradients and custom coloring rules will be applied for easy data analysis. Finally, how to generate custom images in the Database Viewer will be shown.

PSILO / AlphaFold Structures / Macromolecular Repository / Pocket Similarity / Specialized Protein Databases / Visualization

The web-based macromolecular structural analysis and visualization platform, PSILO, now includes the support of a federated database architecture. This permits the seamless integration of multiple data sources for use within the PSILO platform. The inherent modularity of this infrastructure ensures that in silico models can be readily combined with in-house and public structural data, all of which are indexed and available for exploration and analysis within PSILO. In this webinar we will briefly introduce and review this new federated schema. Using a database of AlphaFold models as an example of a federated input source, we will demonstrate how such models are then easily surfaced through executing PSILO queries, are curated and available for pocket similarity searching, and included in the creation of PSILO Project Families.

scFv and Custom Antibody Homology Models / GPU-Acceleration / Hydrogen Mass Repartitioning / Database Viewer Enhancements

MOE’s latest release continues the development of its comprehensive package of applications for computer-aided molecular design. MOE 2022.02 can produce scFv and other custom antibody homology models, and existing applications which include sidechain packing and protein-protein docking, can now make use of GPU-acceleration. Molecular Dynamics and Thermodynamic Integration techniques used either in MOE or through its interface can now benefit from the application of Hydrogen Mass Repartitioning. Graphical enhancements to the MOE database viewer allowing SNFG format carbohydrate notation and data-driven antibody optimization will be described in detail in this webinar.