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

This workshop explores advanced Structure-Based Drug Design (SBDD) workflows for drug discovery projects, covering a broad range of topics from pharmacophore query generation to protein-ligand interaction fingerprints (PLIF). Participants will learn about the application of pharmacophores in protein-ligand docking, scaffold replacement, and R-group screening. Additionally, the workshop will present a method for querying a 3D project database, as well as techniques for generating and analyzing protein-ligand interaction fingerprints (PLIF).

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

Protein-Ligand Interaction Analysis / Protein-Ligand Docking / Pharmacophore Modeling / High-throughput Docking / Template-Based Docking / Covalent Docking

This workshop will cover protein-ligand docking to predict the binding of small-molecule structures to a protein target. Pharmacophore-guided docking will be described as a method to preserve key interactions. Template-based docking will be used to efficiently dock congeneric series of compounds. Reaction-based covalent docking will be used to generate poses for covalently bound ligands. In addition, analysis of docking results and techniques to achieve high-throughput docking will be addressed.

Scaffold Replacement / Ligand Growing / R-group Screening / Bioisosteric Transformations / Pharmacophore Modeling

This workshop will cover fragment-based drug design applications, focusing on methods such as scaffold hopping, fragment growing and R-group exploration to generate novel compound ideas, optimizing and scoring the structures in the pocket. The use of molecular descriptors and pharmacophore models to guide the drug design processes will also be discussed. In addition, an SBDD method for generating closely related analogs through bioisosteric replacements will be presented.

MOEsaic / Matched Molecular Pairs (MMP) Analysis / R-Group Profiles and Analysis / Similarity and Substructure Searching / Molecular Property Analysis / Conformational Searching / Molecular Alignments / Pharmacophore Modeling and Searching

Virtual Screening Compound Libraries / Molecular Descriptors / QSAR/QSPR Modeling / Molecular Fingerprints / Pharmacophore Modeling / Filtering Compound Libraries / Pharmacophore-guided Docking / Template-based Docking / De novo Hit Expansion

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

Scaffold Hopping / Fragment Linking / Ligand Growing / R-Group Screening / Bioisosteric Transformations / Pharmacophore Modeling / Fragment Databases

Protein-Protein Interaction Analysis / Molecular Surfaces / Protein Patch Analysis / Protein Properties / Protein Engineering / Antibody Homology Modeling / Antibody Database / Developability Analysis

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-Ligand Interaction Analysis / Pharmacophore Modeling / Docking / Protein-Ligand Interaction Fingerprints (PLIF) / Fragment-based Design / Scaffold Replacement

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

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).

Structure preparation / Sidechain rotamer exploration / Electron density maps / Solvent analysis with 3D-RISM

The webinar will cover methods for evaluating, analyzing and refining protein models derived from X -ray crystallographic data. Topics related to protein structure preparation and side-chain conformational analysis and placement will be discussed. Visualization and interpretation of electron density maps for assessing protein models will be described. The 3D-RISM method for predicting and refining the placement of solvent molecules in protein models will also be presented.

Structure preparation / Interaction analysis / Patch analysis / Protein contacts / Protein properties / Virtual mutagenesis

The webinar covers methods for analyzing and optimizing peptide-protein interactions in the active site. Using a model system consisting of MDMX protein and a peptide ligand modelled from p53, key contacts and interactions will be identified. Properties of the peptide ligand will be calculated, and opportunities for optimisation of the peptide will be derived by calculating protein patches and other properties for the receptor. We will then see how to mutate the residues in the peptide ligand to optimise binding, both by editing one residue at a time, and by "residue scanning" / virtual mutagenesis, which allows us to investigate the effects of multiple mutations together, thereby identifying beneficial changes.

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.