Machine Learning-Based Virtual Screening of Antibacterial Agents against Methicillin-Susceptible and Resistant Staphylococcus aureus.

The application of computer-aided drug discovery (CADD) approaches has enabled the discovery of new antimicrobial therapeutic agents in the past. The high prevalence of methicillin-resistantStaphylococcus aureus(MRSA) strains promoted this pathogen to a high-priority pathogen for drug development. In this sense, modern CADD techniques can be valuable tools for the search for new antimicrobial agents. We employed a combination of a series of machine learning (ML) techniques to select and evaluate potential compounds with antibacterial activity against methicillin-susceptible S. aureus (MSSA) and MRSA strains. In the present study, we describe the antibacterial activity of six compounds against MSSA and MRSA reference (American Type Culture Collection (ATCC)) strains as well as two clinical strains of MRSA. These compounds showed minimal inhibitory concentrations (MIC) in the range from 12.5 to 200 µM against the different bacterial strains evaluated. Our results constitute relevant proven ML-workflow models to distinctively screen for novel MRSA antibiotics.

Molecular insights on ABL kinase activation using tree-based machine learning models and molecular docking.

Abelson kinase (c-Abl) is a non-receptor tyrosine kinase involved in several biological processes essential for cell differentiation, migration, proliferation, and survival. This enzyme's activation might be an alternative strategy for treating diseases such as neutropenia induced by chemotherapy, prostate, and breast cancer. Recently, a series of compounds that promote the activation of c-Abl has been identified, opening a promising ground for c-Abl drug development. Structure-based drug design (SBDD) and ligand-based drug design (LBDD) methodologies have significantly impacted recent drug development initiatives. Here, we combined SBDD and LBDD approaches to characterize critical chemical properties and interactions of identified c-Abl's activators. We used molecular docking simulations combined with tree-based machine learning models-decision tree, AdaBoost, and random forest to understand the c-Abl activators' structural features required for binding to myristoyl pocket, and consequently, to promote enzyme and cellular activation. We obtained predictive and robust models with Matthews correlation coefficient values higher than 0.4 for all endpoints and identified characteristics that led to constructing a structure-activity relationship model (SAR).