RESUMO
The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target. The PatchSearch web server provides an automated workflow that allows users to identify structurally conserved binding sites at the protein surfaces in a set of user-supplied protein structures. Thus, this web server may help to detect potential off-target protein. It takes as input a protein complexed with a ligand and identifies within user-defined or predefined collections of protein structures, those having a binding site compatible with this ligand in terms of geometry and physicochemical properties. It is based on a non-sequential local alignment of the patch over the entire protein surface. Then the PatchSearch web server proposes a ligand binding mode for the potential off-target, as well as an estimated affinity calculated by the Vinardo scoring function. This novel tool is able to efficiently detects potential interactions of ligands with distant off-target proteins. Furthermore, by facilitating the discovery of unexpected off-targets, PatchSearch could contribute to the repurposing of existing drugs. The server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/PatchSearch.
Assuntos
Drogas em Investigação/química , Proteínas/química , Bibliotecas de Moléculas Pequenas/química , Software , Sequência de Aminoácidos , Animais , Bactérias/química , Sítios de Ligação , Bases de Dados de Compostos Químicos , Conjuntos de Dados como Assunto , Descoberta de Drogas , Drogas em Investigação/farmacologia , Humanos , Internet , Ligantes , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas/agonistas , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Alinhamento de Sequência , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Many therapeutic molecules are known to bind several proteins, which can be different from the initially targeted one. Such unexpected interactions with proteins called off-targets can lead to adverse effects. Potential off-target identification is important to predict to avoid drug side effects or to discover new targets for existing drugs. We propose a new program named PatchSearch that implements local nonsequential searching for similar binding sites on protein surfaces with a controlled amount of flexibility. It is based on detection of quasi-cliques in product graphs representing all the possible matchings between two compared structures. This method has been benchmarked on a large diversity of ligands and on five data sets ranging from 12 to more than 7000 protein structures. The experiments conducted in this study show that the PatchSearch method could be useful in the early identification of off-targets. The program and the benchmarks presented in this paper are available as an R package at https://github.com/MTiPatchSearch .