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.

Protein-Protein Docking / Molecular Surfaces / Protein Patches / Interaction Fingerprints / Clustering / Epitope Analysis

The MOE Protein docking application is used to map epitopes and other protein-protein interfaces (PPI). This automatically calculates a PPI fingerprint for each pose. The poses are clustered using the fingerprint, and epitope residues are identified from the top ranking clusters. The poses can then be annotated in the MOE Window, for browsing through all the top epitopes.

Molecular Fingerprints / Structural Motif Detection / Pharmacophore Queries / Fingerprint Bit Visualization

Reverse fingerprints can be used to detect molecular structure motifs important for a molecular property of interest. This webinar covers the theory of reverse fingerprinting and presents examples of its application to identify pharmacophore motifs and derive consensus pharmacophore queries from a molecular series.

Thermodynamic Integration / Free Energy Calculation / FEP / AMBER / Binding Affinity

Until the advent of GPU accelerated molecular dynamics, alchemical free energy simulations had not been routinely applied in early stage drug discovery. While this GPU acceleration made such calculations more feasible, the complexity of the protocols and uncertainty regarding optimal parameters are a lingering problem. In the recently released MOE 2019 a streamlined interface was added to set up free alchemical energy calculations dynamics simulations based on the Thermodynamic Integration (TI) method in AMBER 18. The workflow includes structure preparation, ligand parameterization, simulation planning and analysis. Free energy calculations are known to be extremely sensitive and have a high failure rate. We present an optimal simulation planning methodology that minimizes the expected error for a given system based on the available simulation resources (number of GPUs, nodes, etc.). Another major source of error is the simulation instability due to an imbalance between the electrostatic and van der Waals forces. Optimization of the AMBER soft-core potential resulted in much higher simulation stability and hence lower curvature of the potential function. In conjunction with Fejér numerical integration the evaluation of the alchemical integral can be achieved with spectral accuracy. The methodology was validated through the calculation of relative binding energies of 34 ligands of the p38 MAP Kinase and compared to experimental data.

Antibody Modeling / Developability Assessment / Solubility and Aggregation Prediction / Titration, pI, and pKa Calculation

mAb candidates identified from high-throughput screening or binding affinity optimization often present liabilities for developability, such as aggregation-prone regions or poor solution behavior. In this work, we developed a method for modeling proteins and performing pH-dependent conformational sampling, which can enhance property calculations such as hydrophobic patches, charge and pI. A retrospective data analysis demonstrates that these 3D descriptors, averaged over conformational sampling and stochastic titration, can accurately predict pI values, screen candidates and enrich libraries with favorable developability properties for a range of biotherapeutics. The clinical landscape of antibodies is also analyzed and its property profile and insights thereof are presented.

Targeted Protein Degradation / PROTACs / Ternary Complex Modeling / Protein-Protein Docking

Targeted protein degradation using bivalent small molecules (such as PROTACs) is a new modality that provides a means to control protein levels in vivo. Despite many clear advantages, numerous challenges exist in PROTAC development, particularly concerning the rational design of efficacious molecules. In this presentation, multiple computational methods that enable the a priori evaluation of putative PROTAC molecules will be discussed. Numerous case studies will be offered, where the application of these computational tools can successfully recommend not only potent PROTAC candidates, but also molecules to avoid. Results from scenarios across different target proteins, E3 ligases, and PROTAC architectures will be presented. Finally, our latest innovations, such as KNIME integration and maximum common substructure matching to simultaneously evaluate multiple PROTAC warheads, will be shown.

Structure Preparation / Force Field / Solvation / AMBER / NAMD / Visualization / Player

Setting up a Molecular Dynamics simulation starting from a protein PDB structure can be challenging. It involves: data preparation, force field parameterization, running protocols and trajectory analysis/visualization. MOE provides a streamlined interface which allows for easy setup, execution and visualization of MD trajectories via AMBER, NAMD or the internal MD engine. In this webinar, the complete workflow to run MD simulations will be introduced.