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

MOE databases / Molecular Descriptors / Sorting and Coloring Plots / Clustering | Diverse Subset Selection / QSAR Modeling / Binary QSAR / Substructure Searching / Molecular Fingerprints / Similarity Searching

Peptide Complex Preparation / Protein-Peptide Interaction Analysis / Surfaces and Maps / Peptide Sequence Optimization / Non-Natural Amino Acids / Conformational Searching / Peptide-Protein Docking / Protein-Peptide Interaction Fingerprints

Protein Alignments and Superposition / Loop and Linker Modeling / Homology Modeling / Protein-Protein Docking / Epitope Analysis / Protein Properties / Protein Solubility Prediction / Protein Patches (2D and 3D) / Biologics QSAR/QSPR Modeling

Scaffold Hopping / Fragment Linking / Ligand Growing / R-Group Screening / Bioisosteric Transformations / Pharmacophore Modeling / Fragment 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 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 molecular surfaces and visualizing protein-protein contacts in 3D. Antibody properties will be evaluated using specialized calculated protein property descriptors and analyzing protein patches. The application of protein engineering tools for affinity and property optimization of antibodies in the context of developability will be studied. Antibody homology modeling optimization examples will include identification of glycosylation sites and their selective modification using a specialized MOE Project antibody database. All the steps necessary for high throughput antibody homology modeling workflow from sequence to structure to property calculations for developability analysis will be described.

Structure Family Search / Protein-Ligand Interaction Fingerprints / MOE Project / Docking / Pharmacophore Modeling

The course describes computational SBDD workflows aimed at advancing medicinal chemistry campaigns. Using real examples, attendees will learn how to search databases of structural families to analyse protein-ligand interaction patterns and use these, and pharmacophore constraints, to guide docking.

Scaffold Replacement / MedChem Transformations / R-Group Screening / Reaction-Guided Library Enumeration

The workshop demonstrates how lead optimization can be advanced by performing scaffold replacement and medchem transformations on a ligand within the context of a receptor pocket. Also, a diverse library of compounds will be enumerated using real chemical reactions using large reagent databases and in-house libraries.

MOE databases / Calculated Descriptors / Fingerprints / QSAR Modeling / Binary QSAR / Similarity Searching / Consensus Modeling

The course will introduce the cheminformatics applications included in MOE, based within its Database Viewer (DBV). Using a dataset of logBB (blood-brain barrier permeation) values, we will import/export data from/to various formats (SDF, SMILES etc.), calculate molecular descriptors, analyse and visualize data, and create QSAR and binary-QSAR models. We will then perform fingerprint-based similarity searching, clustering, diverse subset selection and consensus modeling.

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).

SAR Analysis / Pharmacophores / Psychedelics / Virtual Screening

Psychedelic compounds are powerful substances that alter cognitive and sensory functions. Psilocybin (magic mushrooms), mescaline (peyote cactus) and Lysergic acid diethylamide (LSD) are tryptamine- and phenethylamine-based classical psychedelic compounds which primarily act as agonists and partial agonists against the serotonin 5-HT2A receptors. The overall hallucinogenic properties of psychedelic compounds are highly sensitive to structural features of the compounds and subject to cross-reactivity with monoaminergic receptors. To probe the SAR space of serotonergic hallucinogens, we have applied matched molecular pairs analysis in conjunction with conformational analysis to determine key pharmacophoric elements that contribute to agonist/partial agonist behavior.

Targeted Protein Degradation, Heterobifunctional Degraders / Molecular Glues / Ternary Complex Modeling / Protein-Protein Docking

Targeted protein degradation has emerged in recent years as a new modality to control protein levels in vivo. Among the many competing degradation technologies, most research to date has focused on heterobifunctional protein degraders (such as PROTACs), although inherent concerns about the molecular properties of these “large small molecules” has sparked intense interest in the development of smaller degraders, such as molecular glues. As a rule, molecular glues are smaller and are thus more attractive as potential therapeutics – but because a single molecule is responsible for simultaneously binding to two disparate proteins, the rational discovery of molecular glues to date has proven difficult. In this work, we will discuss multiple computational techniques implemented in MOE for modeling ternary complexes containing molecular glues. Special focus will be paid to lessons learned from our well-established PROTAC modeling toolset. In particular, it will be shown that the most effective molecular glue models result from treating molecular glues as “linkerless PROTACs.” Finally, recent work in developing techniques to prioritize prospective molecular glue designs based on their predicted degradation efficacy will be presented.

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.

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.

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.