Learning Path: Computational Target Analysis

Target analysis is the process of collecting and evaluating all available information concerning a drug discovery target, e.g. its natural occurrence in an organism, its role in biochemical pathways, structure, function, natural variability, known binders or tool compounds, etc. The goal of this stage is to establish a strong understanding of the target which will inform decisions during later stages of a project. While many aspects of this process consist of literature research, computational methods expand the toolbox with which to establish or probe these properties.

VideoHow to find a druggable target: A computational perspectivewebinar.
Online courseTarget enablement, preparation, and validationEnabling protein structures from x-ray crystallography, cryo-EM, ML-methods, and homology modeling for structure-based computational workflows

Prerequisites and preliminary steps

Most methods for computational target analysis require a structure of the target. The more structural information is available, the better (e.g. target bound to various chemical matter as well as apo structures). If no experimentally determined structure is available, structure prediction methods can be used to obtain a usable structure. Ligand-based methods for computational target analysis are very indirect and are not covered here.

Learning PathComputational Structure PredictionSee here for what to do if you don't have a structure.

Assessing overall structure quality

Irrespective where it came from, a structural model can have issues which if left unfixed can adversely impact further calculations. This step usually happens as part of system preparation and is tightly interleaved with it. A variety of tools in the Schrödinger suite can help identify and resolve potential issues. Knowledge and understanding of the system and its biochemistry is essential in this step.

TutorialIntroduction to Structure Preparation and Visualization
TutorialPreparing Nucleic Acid Structureshighlights the particulars for preparing DNA/RNA
DocumentationProtein Reliability ReportCommon structure quality checks
DocumentationBest Practices for Protein Preparation
Quick Reference SheetProtein Preparation Workflow
External websiteRCSB PDB-101 Guide to Understanding PDB Data
VideoEnabling cryoEM structures for drug discovery with the Schrödinger Suite

Work with static structures or use molecular dynamics?

This is not an either-or decision: Making use of both types of methods is helpful.

TutorialUnderstanding and Visualizing Target FlexibilityA few aproaches for identifying flexible regions of a target.

Analyzing static structures

From a single or multiple structures you can get a quick overview of the system and estimate available space. However, this approach is inherently limited by the artificial rigidity imposed on the system.

TutorialTarget Analysis with SiteMap and WaterMapSiteMap is an efficient method for finding and characterizing binding sites from static structure.
TutorialLiability Analysis for BiologicsProtein surface analysis tools useful beyond Biologics applications
TutorialStructure Visualization and Interaction Analysis in Nucleic Acids
TutorialAnalyzing Binding Sites of Nucleic Acids with SiteMapThe scoring function in SiteMap has been recalibrated for improved RNA support.

In-depth analysis using MD methods

MD methods are more computationally costly, but can accurately capture the dynamics of the system and can be used to answer a variety of questions about both the quality of the computational model and the system's behavior in its natural environment. They can be particularly valuable for identifying cryptic or transient binding sites.

TutorialIntroduction to All-Atom Molecular Dynamics Simulations with Desmond
TutorialIntroduction to MD Trajectory Analysis with Desmond
TutorialTarget Analysis with SiteMap and WaterMapWaterMap uses MD simulations to elucidate hydration patterns in binding pockets.
VideoWater matters: Enhancing early drug discovery with insights from water energeticswebinar
VideoIn silico cryptic binding site detection and prioritizationwebinar giving an introduction to mixed-solvent molecular dynamics.
TutorialExploring Protein Binding Sites with Mixed-Solvent Molecular Dynamics

Conclusion and Next Steps

You have done the preliminary work necessary to take stock of the available structural data, understand its pitfalls and limitations and prepare it for modeling. You have analyzed the static structural model to identify key features of the system and/or run MD simulations to understand the dynamics of the system, e.g. the flexibility the protein environment or hydration patterns in a binding pocket. Now, you are ready to use the available structures to answer design questions. Note that it's possible to go back to the tools presented in this stage and re-run them after new information becomes available in a project.

Online courseDesigning quality ligand libraries
Online courseVirtual screening with integrated physics & machine learning
Learning PathVirtual Screening

Workflow