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.

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.

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.

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.