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.

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.

Protein Builder / LowModeMD / Protein Design / Protein Properties / Docking

Cyclic peptides have long been of interest as potential therapeutics, but these “big small molecules” present many challenges for modeling. This Webinar will highlight a number of MOE tools and techniques that can be applied to modeling this class of molecules. Particular attention will be given to the construction of cyclic peptide libraries, including an investigation of their conformational behavior. Approaches to address their chemical stability and permeability will also be discussed. Finally, case studies evaluating the interactions between receptors and both wild-type and rationally designed mutants will be presented.

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.

PSILO / AlphaFold Structures / Macromolecular Repository / Visualization / Pocket Similarity / Project Family / Family Management

MOE Project Families represent a uniquely powerful tool in structure-based drug design. Derived from a carefully curated multi-sequence alignment and a reference file of 3D protein structures that highlights critical structural motifs, these families represent a source of structural insight for drug discovery efforts. When MOE protein families are hosted on the web-based macromolecular structural analysis and visualization platform, PSILO, these ‘PSILO families’ are automatically updated to include recently deposited structures. Following the adoption of a federated database architecture, this enables the seamless integration of both experimental and in silico structures from across the public domain and proprietary sources into PSILO families in a fully automated fashion. Moreover, following a tightened integration between MOE and PSILO, it is now possible to consume PSILO Families directly in MOE - ensuring an evergreen source of protein structural data which is readily available to all via the MOE client application. In this webinar we will briefly introduce PSILO and the creation and maintenance of PSILO Families. We will briefly review the federated database architecture, highlighting how it enables the inclusion of multiple sources (e.g. RCSB, AlphaFold) into the PSILO Family process. Finally, we will demonstrate how to connect MOE and PSILO to enable PSILO functionality directly from within the MOE client, including the surfacing of PSILO Families.

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.