Multi-Target In Silico Prediction of Inhibitors for Mitogen-Activated Protein Kinase-Interacting Kinases

• Tipo: Artigo em Revista Científica Internacional
• Data: 2021

Autores

Halder, AK (Autor) Outra; Natalia N D S Cordeiro (Autor) FCUP

Revista

Título: Biomolecules

Vol. 22

Página Final: 1670

ISSN: 2218-273X

Editora: MDPI

Indexação

ISI Web of Knowledge - 5 Citações

Scopus - 6 Citações

Outras Informações

ID Authenticus: P-00V-P14

DOI: 10.3390/biom11111670

Abstract (EN): The inhibitors of two isoforms of mitogen-activated protein kinase-interacting kinases (i.e., MNK-1 and MNK-2) are implicated in the treatment of a number of diseases including cancer. This work reports, for the first time, a multi-target (or multi-tasking) in silico modeling approach (mt-QSAR) for probing the inhibitory potential of these isoforms against MNKs. Linear and non-linear mt-QSAR classification models were set up from a large dataset of 1892 chemicals tested under a variety of assay conditions, based on the Box-Jenkins moving average approach, along with a range of feature selection algorithms and machine learning tools, out of which the most predictive one (>90% overall accuracy) was used for mechanistic interpretation of the likely inhibition of MNK-1 and MNK-2. Considering that the latter model is suitable for virtual screening of chemical libraries-i.e., commercial, non-commercial and in-house sets, it was made publicly accessible as a ready-to-use FLASK-based application. Additionally, this work employed a focused kinase library for virtual screening using an mt-QSAR model. The virtual hits identified in this process were further filtered by using a similarity search, in silico prediction of drug-likeness, and ADME profiles as well as synthetic accessibility tools. Finally, molecular dynamic simulations were carried out to identify and select the most promising virtual hits. The information gathered from this work can supply important guidelines for the discovery of novel MNK-1/2 inhibitors as potential therapeutic agents.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 17