Hybrid Methods

Hybrid methods are the integrated VS methods that depend on both structural and ligand similarity. They use all available chemical and biological information and enhance the strengths and reduce the drawbacks of each individual VS method, thereby resulting in more successful computer-aided drug design. Hybrid methods predict small-molecule binders based on evolution-based ligand-binding information and use both global structural similarity and pocket similarity.

Figure 1. Workflow of combined ligand- and structure-based approaches. (A) Hierarchical virtual screening (HLVS). (B) Parallel virtual screening (PVS). (Methods. 20151)

Profacgen provides different strategies for integration of ligand- and structure-based virtual screening methods, which can be divided into hierarchical, parallel and hybrid approaches. In hybrid virtual screening, both structural and ligand information is combined into a standalone method. This method has been developed and used successfully in many cases. The protein-ligand pharmacophores are applied to represent a combination of ligand- and protein-information as they are developed based on experimental structures or homology models of protein-ligand complexes. Excluded volumes are used to restrict filtered compounds to the size of binding pocket.

In our hierarchical virtual screening services, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. Computationally inexpensive ligand-based approaches such as similarity search are used during initial steps of HLVS. Methods demanding relatively high computational resources such as molecular docking are used once the number of compounds to be screened decreases to a reasonable number. The final step incorporates the visual selection of compounds by our expertise, where ranking from VS methods is more accurate with both literature-based knowledge and our expert chemical intuition.

Our advantages

1. Combination of ligand- and structure-based virtual screening methods
2. Hierarchical, parallel, and hybrid virtual screening
3. Protein-ligand pharmacophore modeling
4. Integration of proficient visual selection

Reference:

[1] Kumar, A.; Zhang, K. Y., Hierarchical virtual screening approaches in small molecule drug discovery. Methods 2015, 71, 26-37.