Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

BACKGROUND: Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) participates in the reabsorption of 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. OBJECTIVE: The aim in this work was to obtain new potential SGLT2 inhibitors. METHODS: A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. RESULT: A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived of spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. CONCLUSION: These compounds are proposed as potential SGLT2 inhibitors.

Analysis of Giardia lamblia Nucleolus as Drug Target: A Review.

Giardia lamblia (G. lamblia) is the main causative agent of diarrhea worldwide, affecting children and adults alike; in the former, it can be lethal, and in the latter a strong cause of morbidity. Despite being considered a predominant disease in low-income and developing countries, current migratory flows have caused an increase in giardiasis cases in high-income countries. Currently, there is a wide variety of chemotherapeutic treatments to combat this parasitosis, most of which have potentially serious side effects, such as genotoxic, carcinogenic, and teratogenic. The necessity to create novel treatments and discover new therapeutic targets to fight against this illness is evident. The current review centers around the controversial nucleolus of G. lamblia, providing a historical perspective that traces its apparent absence to the present evidence supporting its existence as a subnuclear compartment in this organism. Additionally, possible examples of ncRNAs and proteins ubiquitous to the nucleolus that can be used as targets of different therapeutic strategies are discussed. Finally, some examples of drugs under research that could be effective against G. lamblia are described.

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

Benzoic Acid Derivatives with Trypanocidal Activity: Enzymatic Analysis and Molecular Docking Studies toward Trans-Sialidase.

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS) inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19) sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC50) was <0.15 µM on the NINOA strain, and LC50 < 0.22 µM on the INC-5 strain. Additionally, compound 18 showed a moderate inhibition (47%) on the trans-sialidase enzyme and a binding model similar to DANA (pattern A).

Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives.

In this work, a novel series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated in vitro on Trypanosoma cruzi trypomastigotes and Leishmania mexicana promastigotes, and cytotoxicity activity in murine macrophages was tested. In silico molecular docking simulations of trypanothione reductase were also done. Three compounds of 33 quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better anti-T. cruzi activity than nifurtimox and beznidazole; two compounds had better anti-leishmanial activity that amphotericin-B, and two compounds showed better activity against both parasites than reference drugs. Compounds M2, M7, M8 and E5, showed low cytotoxic activity on the host cell. The in silico studies suggest that compound M2 is a potential trypanothione reductase inhibitor.