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

The course 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 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).

R-Group Profiles and Analysis / MOEsaic / MMP Analysis / Descriptor Calculations / Conformational Searching / Molecular Alignments / Pharmacophore Modeling and Searching / Diversity Analysis

The course covers essential in silico methods needed for guiding drug discovery projects in the absence of a protein structure. Analysis of SAR through R-group profiling and matched molecular pairs (MMP) analysis using MOEsaic to determine relationships among a chemical series are examined. Molecular descriptor calculations and their application for determining property correlations along with diversity analysis are described. Molecular alignments and conformational analyses of a congeneric series are explored to assess the impact of ligand substituents. An approach for developing pharmacophore queries is discussed. Management and manipulation of MOE databases are also covered.

MOE Databases / Descriptors / Fingerprints / QSPR Modeling / Pharmacophore Modeling / Template-Forced Docking / Scaffold Replacement / MedChem Transformations

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.

Protein Alignments and Superposition / Loop and Linker Modeling / Homology Modeling / Protein- Protein Docking / Protein Solubility Analysis / 2D Hot Spot Mapping / PLIF / Biologics QSAR Modeling

The course covers methods for aligning protein sequences, superposing structures, homology modeling fusion proteins and conducting protein-protein docking. In particular, an approach for aligning and superposing 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.

MOEsaic / R-Group Profiles and Analysis / MMP Analysis / Similarity and Substructure Searching / Descriptor Calculations / Conformational Searching / Molecular Alignments / Pharmacophore Modeling and Searching

The course covers essential in silico methods needed for guiding drug discovery projects in the absence of a protein structure. Analysis of SAR through R-group profiling and matched molecular pairs (MMP) analysis using MOEsaic to determine relationships among a chemical series are examined. Molecular descriptor calculations and their application for determining property correlations are described. Molecular alignments and conformational analyses of a congeneric series are explored to assess the impact of ligand substituents. An approach for developing pharmacophore queries is discussed. Management and manipulation of MOE databases are also covered.

Structure-based drug design, aided by computational methods, is now well established as a key discipline in the discovery of new medicines. The workshop will illustrate a range of computational techniques for SBDD, covering some related areas such as docking, and analysis of SAR data in case protein-ligand crystal structural information is not available, through demonstration using the MOE software.

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

Docking / Fragment-based Design / Scaffold Replacement / R-Group Screening / Project Search / Protein-Ligand Interaction Fingerprints / MOEsaic / MMP Analysis

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

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).

Molecular Surfaces and Maps / Ligand Interactions / Conformational Searching / 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. Conformational searching and analysis of the ligand to assess ligand flexibility will be discussed. A protocol for aligning and superposing protein complexes in the context of protein selectivity will be studied.

Ensemble protein properties / bispecific antibodies / CDR grafting / high-throughput homology modeling

We will present and demonstrate the new biologics features in MOE 2019.01. These include pH dependent ensemble protein property calculations, bispecific antibody modeling and advanced CDR grafting as well as high-throughput protein homology modeling. Various other related new features will also be discussed.

AMBER Thermodynamic Integration / Relative Free Energy of Binding / NMR Conformation Distributions / MOEsaic - SAR Explorer / Pairwise Analysis of MMPs / Ion channels

We will introduce the new capabilities in the latest version of the MOE software release which includes running AMBER Thermodynamic Integration (TI) from MOE and subsequent analysis as well as predicting solution phase NMR conformation distribution. We will also describe enhancements to MOEsaic - SAR Explorer which include customizing project configurations and property models, MOEsaic session updating and sharing, virtual compound design with integrated sketcher and pair mode analysis.