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).

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.

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.

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.

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.

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.

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

The workshop describes SBDD workflows in drug discovery projects and encompasses a range of topics from pharmacophore query generation to protein-ligand interaction fingerprints. More specifically, the workshop 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).

Virtual Screening Compound Libraries / Descriptors, Fingerprints and QSPR Modeling / Pharmacophore Modeling / Template-based Docking / Compound Design

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.

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.

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.

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.

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.

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.

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.

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.