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.

Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity.

Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models was established to optimize the 2-thiazolylhydrazone skeleton and obtain novel compounds with higher potency, better solubility in water, and enhanced absorption. Twenty-nine novel compounds were obtained and most showed low micromolar MIC values against different species of Candida and Cryptococcus spp., including Candida auris, an emerging multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 µM) was selected for further studies: cytotoxicity evaluation, permeability study in Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection model. All results obtained indicate the great potential of 28 as a novel antifungal agent.

The Brazilian compound library (BraCoLi) database: a repository of chemical and biological information for drug design.

The Brazilian Compound Library (BraCoLi) is a novel open access and manually curated electronic library of compounds developed by Brazilian research groups to support further computer-aided drug design works, available on https://www.farmacia.ufmg.br/qf/downloads/ . Herein, the first version of the database is described comprising 1176 compounds. Also, the chemical diversity and drug-like profiles of BraCoLi were defined to analyze its chemical space. A significant amount of the compounds fitted Lipinski and Veber's rules, alongside other drug-likeness properties. A comparison using principal component analysis showed that BraCoLi is similar to other databases (FDA-approved drugs and NuBBEDB) regarding structural and physicochemical patterns. Furthermore, a scaffold analysis showed that BraCoLi presents several privileged chemical skeletons with great diversity. Despite the similar distribution in the structural and physicochemical spaces, Tanimoto coefficient values indicated that compounds present in the BraCoLi are generally different from the two other databases, where they showed different kernel distributions and low similarity. These facts show an interesting innovative aspect, which is a desirable feature for novel drug design purposes.

Machine learning techniques applied to the drug design and discovery of new antivirals: a brief look over the past decade.

Introduction: Drug design and discovery of new antivirals will always be extremely important in medicinal chemistry, taking into account known and new viral diseases that are yet to come. Although machine learning (ML) have shown to improve predictions on the biological potential of chemicals and accelerate the discovery of drugs over the past decade, new methods and their combinations have improved their performance and established promising perspectives regarding ML in the search for new antivirals.Areas covered: The authors consider some interesting areas that deal with different ML techniques applied to antivirals. Recent innovative studies on ML and antivirals were selected and analyzed in detail. Also, the authors provide a brief look at the past to the present to detect advances and bottlenecks in the area.Expert opinion: From classical ML techniques, it was possible to boost the searches for antivirals. However, from the emergence of new algorithms and the improvement in old approaches, promising results will be achieved every day, as we have observed in the case of SARS-CoV-2. Recent experience has shown that it is possible to use ML to discover new antiviral candidates from virtual screening and drug repurposing.

Cytotoxic Activity of Triterpenoids from Cheiloclinium cognatum Branches against Chronic and Acute Leukemia Cell Lines.

Cheiloclinium cognatum (Miers) A.C.Sm. is an endemic species of Brazilian Cerrado that belongs to Celastraceae family. The phytochemical study of C. cognatum branches led to the identification of ten triterpenoids (TPs), 3ß-acyloxyurs-12-ene (1), friedelin (2), ß-friedelinol (3), glut-5-en-3ß-ol (4), α-amyrin (5), ß-amyrin (6), ß-sitosterol (7), canophyllol (8), 29-hydroxyfriedelan-3-one (9) and friedelane-3ß,29-diol (10). TPs 4, 5 and 6 are described for the first Cheiloclinium genus and TPs 8 and 9 were isolated in expressive amounts. Their cytotoxic activities were evaluated against THP-1 and K562 leukemia cell lines. TPs 3 and 5 were the most active, exhibiting lower or similar IC50 against both cell lines when compared to the controls. Their mechanisms of action were investigated suggesting an intrinsic mitochondrial pathway of apoptosis evidenced by up-regulation of BAK mRNA expression. Chemometric studies indicated that their activities may be related to their molecular size and shape as well as electronic interactions of C-3 hydroxy group with molecular targets.