Introduction

Virtual Screening (VS) has become an important field in modern drug-discovery, which has mainly arisen from the increased pressure of reducing the cost of lead discovery. Currently there are two approaches to VS: ligand-based and the structure-based (docking) methods. Structure-based VS methods rely on the structural similarity between the target and the query molecule. Due to the fact that 2D fingerprints can be generated in a fast and easy way, structure-based VS methods are usually based on 2D similarity calculations. However, 2D approaches often have limitations, such as the lack of real structural insight. Therefore, 3D VS methods have been developed that also provide molecular alignments, helping e.g. pharmacophore analysis in the process of lead optimization. These methods use 3D structural similarity of the query and target pair to perform the screening.

Screen3D is a command line tool for fast 3D ligand-based virtual screening.

General information

To calculate 3D similarity for the query and target pair, Screen3D uses the flexible 3D Alignment module. The input molecule need not to have 3D coordinates; if 2D input structures are used, initial 3D conformers are automatically generated. Both molecules can be treated conformationally either rigid or flexible. In the first case the original conformation is kept during the alignment process. In the second case, the dihedral bonds of the molecule are able to freely rotate, so the conformation of the molecule changes during the superposition step.

The result of the similarity calculation is the aligned pair of the query and the target, and the their similarity score. This is then used for ranking.

There are two types of similarity calculations available in Screen3D:

• Shape method: this method superimposes molecules based on their 3D shape. Molecular shapes are represented by mathematical functions and the shape is coloured by attributed atom types. Atom typization can be based on ChemAxon's Dreiding force field or on pharmacophore typization.

• Match method: this method is based on the systematic matching of atoms to be aligned.

Both methods work in two phases:

• Input data generation: this phase "prepares" the query and target molecules for the alignment process. It calculates the shape functions, performs the necessary atom typization etc. The output of this phase are two files: a binary file used in the second phase and a molecule file to view the 3D structure.

• Screening phase: this phrase performs the actual screening. The output of this phase is different similarity-related data (unnormalized and Tanimoto similarity) in a text format and a structure file with the aligned target structures.

Details on how these methods work (and when and how they are applicable) can be found in the reference article.

Usage example

The following simple workflow shows how to use the Screen3D command line tool. All options of the command line tool can be seen by running

References

1. Kalászi, A.; Szisz D.; Imre G.; Polgár T., Screen3D: A Novel Fully Flexible High-Throughput Shape-Similarity Search Method. J. Chem. Inf. Model. , 2014 , 54 (4), pp 1036–1049