Drug repurposing combined with MM/PBSA based validation strategies towards MEK inhibitors screening

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Abstract

Emergence of oncogenic mutations in the MAPK pathway gaining more impact in the recent years. Importantly, MEK is a core element of this pathway as it is easy to inhibit and is a gatekeeper of multiple malignancies. Therefore, we performed in-silico strategy to screen repurposed candidate for MEK protein using a library of 11,808 compounds from different clusters in the DrugBank database. Glide docking, Prime-MM/GBSA and QikProp analysis were implemented to retrieve the hits with high precision. The stability of the binding mode and binding affinity of the resultant hit were explored using molecular dynamic simulations and MM/PBSA approach. The results highlight that Nebivolol (DB04861) not only achieved a stable conformation in the MEK binding pocket but also displayed highest binding affinity than the other molecules investigated in our study. Taken together, we hypothesized that Nebivolol is an excellent candidate for the inhibition of MEK in NSCLC patients in future.Communicated by Ramaswamy H. Sarma.

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DrugBank 5.0: a major update to the DrugBank database for 2018

David S Wishart, Yannick D Feunang, An C Guo … (2017)

Abstract DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year’s update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.

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PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.

Alexander Schüttelkopf, Daan M F van Aalten (2004)

The small-molecule topology generator PRODRG is described, which takes input from existing coordinates or various two-dimensional formats and automatically generates coordinates and molecular topologies suitable for X-ray refinement of protein-ligand complexes. Test results are described for automatic generation of topologies followed by energy minimization for a subset of compounds from the Cambridge Structural Database, which shows that, within the limits of the empirical GROMOS87 force field used, structures with good geometries are generated. X-ray refinement in X-PLOR/CNS, REFMAC and SHELX using PRODRG-generated topologies produces results comparable to refinement with topologies from the standard libraries. However, tests with distorted starting coordinates show that PRODRG topologies perform better, both in terms of ligand geometry and of crystallographic R factors.