In silico drug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets against Mycobacterium Tuberculosis

• Published in: bioRxiv
• Main Authors: Kirsten Elke Knoll, Mietha M Van Der Walt, Du Toit Loots
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.11.2021
• Subjects: Antibiotics; Antimicrobial agents; Bioavailability; Cell walls; Clinical trials; Drug development; Drug discovery; Drug screening; Metabolic pathways; Molecular modelling; Pharmacokinetics; Safety; Therapeutic targets; Toxicity; Tuberculosis
• DOI: 10.1101/2021.11.17.469062

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation, we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the thirteen identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated to the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041's activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication.