Molecular Graphics / Visual Effects / Publication-Quality Images

This webinar covers the advanced graphics capabilities of MOE. Topics include how to render molecular objects and surfaces, display property maps and grid, adjust the lighting, backgrounds and visual effects of an image, and how to produce publication-quality image files. Advanced topics include exporting to 3D printers and other embedded 3D file formats.

Automated Pharmacophore Generation / Binding Site Analysis / Protein Ensembles

An automated approach to summarize pocket shapes and binding hot-spots from a collection of protein structures is presented. Pocket shapes are described using pocket volumes derived from Alpha Sites and molecular surfaces. Binding hot-spots are located using pharmacophore features generated by AutoPH4. Collections of pocket volumes and pharmacophores are analyzed using feature densities which map onto a universal grid the fraction of structures that possess a given feature at each point in space. Regions with high pharmacophore feature densities identify the most persistent interaction binding hot-spots over the collection of structures. Pocket volume densities detect and classify binding site regions into core pockets and sub-pocket regions. Fingerprints that represent pocket shape, sub-pocket presence and pharmacophore feature presence are derived and used to cluster and classify multiple protein structures using standard fingerprint clustering tools. Application of the method to fragment-based drug design, minor pocket detection, selectivity mapping, binding-mode classification and custom docking scoring function creation is presented.

Antibody Modeling / Developability / Liability / Aggregation

Antibody candidates often have poor biophysical properties and/or chemical liabilities that cause downstream developability issues. In this demonstration, we will model a mouse antibody and identify liability motifs using such as glycosylation PTM sites and we will propose statistically appropriate mutations. We will then model a panel of 14 IgG4 candidates and select one for improved developability in terms of aggregation and solubility using high-throughput antibody modeling and property calculations.

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.

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.

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.

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.

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.

Structure Preparation / Protein-Peptide Interaction Analysis / Conformational Searching / Protein-Peptide Docking / Protein-Ligand Interaction Fingerprints

The course will cover methods for protein-peptide interaction analysis, and protein-peptide docking. Conformational searching of peptide structures will also be discussed, and a method for identifying contact points using Protein-Ligand Interaction Fingerprints (PLIFs) will be described.

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.

Molecular Fingerprints / Structural Motif Detection / Pharmacophore Queries / Fingerprint Bit Visualization

Reverse fingerprints can be used to detect molecular structure motifs important for a molecular property of interest. This webinar covers the theory of reverse fingerprinting and presents examples of its application to identify pharmacophore motifs and derive consensus pharmacophore queries from a molecular series.