Virtual Screening: A Step-by-Step Guide for Researchers

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Introduction to Virtual Screening


What is Virtual Screening?

Virtual screening (VS) refers to a method based on the theory of drug design, with the help of computer technology and professional application software, to select some promising compounds from a large number of compounds, and to evaluate the experimental activity. New lead compounds are screened out of tens or even millions of molecules.


Types of Virtual Screening

In principle, virtual screening can be divided into two categories, namely receptor-based virtual screening and ligand-based virtual screening.


Receptor-based virtual screening

Receptor-based virtual screening is also known as structure-based virtual screening (SBVS). Using molecular docking technology, based on the three-dimensional structure of the receptor, the small molecules in the compound database are automatically matched at the binding site, and then, the scoring function based on the molecular force field is used to calculate the binding energy of the possible binding modes, and finally the energy ranking of the compounds is obtained.


Advantages and Disadvantages of Receptor-based virtual screening

Compared with ligand-based virtual screening, its advantage is that it can avoid activity changes caused by small structural changes of active compounds, but there are also some shortcomings:


  1. The biggest problem is the accuracy and applicability of the scoring function. Generally, considering the calculation speed, a relatively simple scoring function is usually used, but the simple scoring function cannot take into account the weaker interaction;


  1. Receptor-based virtual screening requires receptor structures and designated binding sites, but many important targets do not have available receptor structures;


  1. And there are problems that need to be solved in molecular docking including: molecular flexibility, melting agent effect and scoring function.


Ligand-based virtual screening

Ligand-based virtual screening (LBVS) methods predict activity by measuring the similarity of the compounds in the library to reference compounds that are active against a target of interest. 2D or 3D chemical structures or molecular descriptors of known actives are used to retrieve other (‘similar”) compounds of interest in a database using various types of similarity measures or by seeking a common substructure or pharmacophore between the query molecules and the scanned libraries.


Advantages of Ligand-based virtual screening

Due to the fact that LBVS does not use macromolecules in its calculations and does not necessitate any prior knowledge of active ligands, it has a number of advantages over other virtual screening methods. When three-dimensional structures of potential drug targets are unavailable, it is one of the most preferred approaches for drug discovery and lead optimization.


Ligand-based methods are based on the principle that structure determines properties. Such methods include:


  1. Pharmacophore modeling

Pharmacophore modeling is to conduct pharmacophore research on a series of known active compounds, and to obtain some groups that play a key role in the activity of compounds through conformational analysis, molecular superposition and other methods. information;


  1. Quantitative structure activity relationship (QSAR)

Quantitative structure activity relationship (QSAR) is a method to quantitatively study the interaction between small organic molecules and biological macromolecules, and the absorption, distribution, metabolism, excretion and other physiologically relevant properties of small organic molecules in organisms by means of physical and chemical property parameters or structural parameters of molecules.


  1. Structural similarity (SSIM)

Structural similarity (SSIM) is to perform similarity matching through various descriptors or fingerprints, so as to judge whether compounds have similar activities or therapeutic mechanisms.

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