Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations.

BACKGROUND: Neglected tropical diseases (NTDs) are parasitic and bacterial diseases that affect approximately 149 countries, mainly the poor population without basic sanitation. Among these, African Human Trypanosomiasis (HAT), known as sleeping sickness, shows alarming data, with treatment based on suramin and pentamidine in the initial phase and melarsoprol and eflornithine in the chronic phase. Thus, to discover new drugs, several studies point to rhodesain as a promising drug target due to the function of protein degradation and intracellular transport of proteins between the insect and host cells and is present in all cycle phases of the parasite. METHODOLOGY: Here, based on the previous studies by Nascimento et al. (2021) that show the main rhodesain inhibitors development in the last decade, molecular docking and dynamics were applied in these inhibitors datasets to reveal crucial information that can be into drug design. Thus, conventional and covalent docking was employed and highlighted the presence of Michael acceptors in the ligands in a peptidomimetics scaffold, and interaction with Gly19, Gly23, Gly65, Asp161, and Trp184 is essential to the inhibiting activity. RESULTS: Also, our findings using MD simulations and MM-PBSA calculations confirmed Gly19, Gly23, Gly65, Asp161, and Trp184, showing high binding energy (ΔGbind between -72.782 to -124.477 kJ.mol-1). In addition, Van der Waals interactions have a better contribution (-140,930 to -96,988 kJ.mol-1) than electrostatic forces (-43,270 to -6,854 kJ.mol-1), indicating Van der Waals interactions are the leading forces in forming and maintaining ligand-rhodesain complexes. CONCLUSION: Furthermore, the Dynamic Cross-Correlation Maps (DCCM) show more correlated movements for all complexes than the free rhodesain and strong interactions in the regions of the aforementioned residues. Principal Component Analysis (PCA) demonstrates complex stability corroborating with RMSF and RMSD. This study can provide valuable insights that can guide researchers worldwide to discover a new promising drug against HAT.

Overview of the New Bioactive Heterocycles as Targeting Topoisomerase Inhibitors Useful Against Colon Cancer.

Colorectal cancer (CRC) is the third most common worldwide cancer with high mortality. Factors such as more effective screening programs and improvements in treatment modalities have favored a decrease in the incidence and mortality rate of colorectal cancer in the last three decades. Metastatic CRC is incurable in most cases, and therapy using multiple drugs can increase patients' life expectancy by 2 to 3 years. Chemotherapy is the primary treatment, and fluoropyrimidines correspond to the first treatment line. They can be used in monotherapy or therapeutic schemes of oxaliplatin, FOLFOX (intravenous fluorouracil, leucovorin, and oxaliplatin), and CAPOX (oral capecitabine and oxaliplatin) or regimens based on Irinotecan, such FOLFIRI (fluorouracil, leucovorin, and Irinotecan) and CAPIRI (capecitabine and Irinotecan). Like Camptothecin, irinotecan and other analogs have a mechanism of action based on forming a ternary complex with Topoisomerase I and DNA by reversibly binding, providing DNA damage and consequent cell death. This way, topoisomerases are vital enzymes for DNA maintenance and cell viability. Thus, here we will review the main works demonstrating the correlation between the inhibition of different isoforms of topoisomerases and the in vitro cytotoxic activity in colon cancer. The findings revealed that natural compounds, semi-synthetic and synthetic analogs showed potential cytotoxicity against several colon cancer cell lines in vitro and that this activity was often accompanied by the ability to inhibit type I and II topoisomerases, demonstrating that these enzymes can be promising drug targets for the development of new chemotherapeutics against colon cancer.

Topoisomerase Enzyme Inhibitors as Potential Drugs Against Cancer: What Makes Them Selective or Dual? - A Review.

Topoisomerase inhibitors are extensively used in cancer chemotherapy. In the process of identifying novel anticancer compounds, biological evaluations are crucial and include, among others, the use of in silico and in vitro approaches. This work aimed to present recent research involving the obtainment and in silico and in vitro evaluation of topoisomerase I, II, and double inhibitors, of synthetic and natural origin, as potential compounds against tumor cells, in addition to proposing the construction of a desirable enzyme catalytic site. Therefore, it was observed that most Topoisomerase I inhibitors presented medium to large structures, with a rigid portion and a flexible region. In contrast, Topoisomerase IIα inhibitors showed medium and large structural characteristics, in addition to the planarity of the aromatic rings, which are mitigated due to flexible rings but may also present elements that restrict conformation. Most compounds that exhibit dual inhibitory activity had relatively long chains, in addition to a flat and rigid portion suggestive of affinity for Topo I and a flexible region characteristic of selective drugs for Topo II. Besides, it is noticed that most compounds that exhibit dual inhibitory showed similarities in the types of interactions and amino acids when compared to the selective compounds of Topo I and II. For instance, selective Topoisomerase I inhibitors interact with Arginine364 residues, and selective Topoisomerase II inhibitors interact with Arginine487 residues, as both residues are targets for dual compounds.

Application of Heterocycles as an Alternative for the Discovery of New Anti-ulcer Compounds: A Mini-Review.

A peptic ulcer is a lesion located in the esophagus, stomach, and upper intestine, caused by an imbalance between acid secretion and the release of protective mucus. This pathology is prevalent in approximately 14% of the world population and is commonly treated with proton pump inhibitors and type 2 histaminergic receptor antagonists, however, these drugs present concerning side effects that may lead to gastric cancer. In this sense, this research aimed to present the main heterocyclics studied in recent years. The screening method for the choice of articles was based on the selection of publications between 2000 and 2021 present in the Science Direct, Web of Science, Capes, and Scielo databases, by using the descriptors ''new derivatives'', "heterocyclics" "antiulcerogenic", "gastroprotective" and "antisecretor". This research showed that the most used rings in the development of anti-ulcer drugs were benzimidazole, quinazoline, thiazole, and thiadiazole. The results also portray several types of modern in silico, in vitro and in vivo assays, as well as the investigation of different mechanisms of action, with emphasis on proton pump inhibition, type 2 histaminergic receptor blockers, potassium competitive acid blockers, type E prostaglandin agonism, anti-secretory activity and anti-oxidant action. Additionally, the review evidenced the presence of the nitrogen atom in the heterocyclic ring as a determinant of the potential of the compound. This research suggests new alternatives for the treatment of gastric lesions, which may be more potent and cause fewer side effects than the currently used, and tend to evolve into more advanced studies in the coming years.