flowchart TD
step_Computational_Target_Analysis["Computational Target Analysis"]
step_Prerequisites_and_preliminary_steps("Prerequisites and preliminary steps")
step_Assessing_overall_structure_quality("Assessing overall structure quality")
step_Work_with_static_structures_or_use_molecular_dynamics{{"Work with static structures or use molecular dynamics?"}}
step_Analyzing_static_structures("Analyzing static structures")
step_In_depth_analysis_using_MD_methods("In-depth analysis using MD methods")
step_Conclusion_and_Next_Steps("Conclusion and Next Steps")
step_Computational_Target_Analysis --> step_Prerequisites_and_preliminary_steps
step_Prerequisites_and_preliminary_steps --> step_Assessing_overall_structure_quality
step_Assessing_overall_structure_quality --> step_Work_with_static_structures_or_use_molecular_dynamics
step_Work_with_static_structures_or_use_molecular_dynamics --> |"Analyze a static structure"| step_Analyzing_static_structures
step_Work_with_static_structures_or_use_molecular_dynamics --> |"Use molecular dynamics"| step_In_depth_analysis_using_MD_methods
step_Analyzing_static_structures --> step_Conclusion_and_Next_Steps
step_In_depth_analysis_using_MD_methods --> step_Conclusion_and_Next_Steps
classDef path_title stroke-width:2px,fill:#12122c,stroke:#12122c
classDef decision_step stroke-width:2px,fill:#005aaa,stroke:#005aaa
classDef simple_step stroke-width:2px,fill:#12122c,stroke:#12122c
class step_Computational_Target_Analysis path_title
class step_Prerequisites_and_preliminary_steps,step_Assessing_overall_structure_quality,step_Analyzing_static_structures,step_In_depth_analysis_using_MD_methods,step_Conclusion_and_Next_Steps simple_step
class step_Work_with_static_structures_or_use_molecular_dynamics decision_step
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.
Enabling protein structures from x-ray crystallography, cryo-EM, ML-methods, and homology modeling for structure-based computational workflows
Next step: Prerequisites and preliminary steps
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.
See here for what to do if you don't have a structure.
Next step: Assessing overall structure quality
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.
highlights the particulars for preparing DNA/RNA
Common structure quality checks
Next step: Work with static structures or use molecular dynamics?
Decide: Work with static structures or use molecular dynamics?
This is not an either-or decision: Making use of both types of methods is helpful.
A few aproaches for identifying flexible regions of a target.
- Analyze a static structure: go to Analyzing static structures
- Use molecular dynamics: go to In-depth analysis using MD methods
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.
SiteMap is an efficient method for finding and characterizing binding sites from static structure.
Protein surface analysis tools useful beyond Biologics applications
Next step: Conclusion and Next Steps
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.
WaterMap uses MD simulations to elucidate hydration patterns in binding pockets.
Next step: Conclusion and Next Steps
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.