RNA Modeling / Capture Design Ideas / AMBER:EHT Forcefield / High-Throughput Biologics Screening / R-group-Activity-Relationship Heatmaps / Predict ECD and ORD

CCG is pleased to announce the 2024 release of the Molecular Operating Environment, MOE. In this webinar we will present new features and enhancements in MOE 2024.06, extending the suite of computer-aided molecular design applications to include: Capture - Document and Share Design Sessions / Pharmacophore-guided High-throughput Biologics Virtual Screening / Map 2D Protein Patch Differences and Ensemble Averages / Updated Amber: EHT Forcefield Parameters from Atom Hybridization Character / Predict ECD and ORD Spectra to Determine Stereochemistry and Conformational Ensembles / Support for Non-natural RNA Bases, Ribose Backbones, and Ionization/Tautomeric States / Interactive Database Viewer Property Filter

Forcefield Parametrization / Forcefield Development / Forcefield Validation / Atom-type Free Parametrization / AmberEHT Forcefield

A new methodology to determine bonded forcefield parameters is presented. A coordinate-free Hückel calculation is the basis for chemical perception and the results are used in combination with physical chemistry relationships to determine parameters for bond lengths, angles and torsions (with associated force constants). Comparisons to quantum mechanical torsion profiles are presented to validate the resulting parameterizations.

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.

The Japanese MOE Forum is a free online UGM event organized by MOLSIS, a distributor of MOE for Asia. Guest speakers from Japan and China will deliver scientific talks on diverse topics, while application scientists from Chemical Computing Group and MOLSIS will present the latest updates on MOE and PSILO. The event also includes scientific poster sessions, MOE and PSILO demonstrations, and virtual networking. Presentations will be in English, Japanese, or Chinese, with simultaneous interpretation available. Video recordings allowed by the speakers will be made available to registered attendees only.

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.