Quantum mechanics insights into melatonin and analogs binding to melatonin MT1 and MT2 receptors.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

Novel computational and drug design strategies for the inhibition of human T-cell leukemia virus 1-associated lymphoma by Astilbin derivatives.

Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein-ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds' charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma.Communicated by Ramaswamy H. Sarma.

Caffeic Acid Has Antiviral Activity against Ilhéus Virus In Vitro.

Ilhéus virus (ILHV) is a neglected mosquito-borne flavivirus. ILHV infection may lead to Ilhéus fever, an emerging febrile disease like dengue fever with the potential to evolve into a severe neurological disease characterized by meningoencephalitis; no specific treatments are available for this disease. This study assessed the antiviral properties of caffeic acid, an abundant component of plant-based food products that is also compatible with the socioeconomic limitations associated with this neglected infectious disease. The in vitro activity of caffeic acid on ILHV replication was investigated in Vero and A549 cell lines using plaque assays, quantitative RT-PCR, and immunofluorescence assays. We observed that 500 µM caffeic acid was virucidal against ILHV. Molecular docking indicated that caffeic acid might interact with an allosteric binding site on the envelope protein.

Virtual screening of small natural compounds against NS1 protein of DENV, YFV and ZIKV.

Diseases caused by viruses of the genus Flavivirus are among the main diseases that affect the world and they are a serious public health problem. Three of them stand out: Dengue, Yellow fever and Zika viruses. The non-structural protein 1 (NS1), encoded by this viral genus, in its dimeric form, plays important roles in the pathogenesis and RNA replication of these viruses. Therefore, the identification of chemicals with the potential to inhibit the formation of the NS1 protein dimer of DENV, YFV and ZIKV would enable them to act as a multi-target drug. For this, we selected conformations of the NS1 protein monomer with similar ß-roll domain structure among the three virus species from conformations obtained from molecular dynamics simulations performed in GROMACS in 5 replicates of 150 ns for each species. After selecting the protein structures, a virtual screening of compounds from the natural products catalog of the ZINC database was performed using AutoDock Vina. The 100 best compounds were classified according efficiency criteria. Two compounds were observed in common to the species, with energy scores ranging from -9.2 kcal/mol to -10.1 kcal/mol. The results obtained here demonstrate the high similarity of NS1 proteins in the Flavivirus genus and high affinity for the same compounds; thus justifying the potential of these small molecules act in multitarget therapy.Communicated by Ramaswamy H. Sarma.

Mycobacterium bovis PknG R242P Mutation Results in Structural Changes with Enhanced Virulence in the Mouse Model of Infection.

Mycobacterium bovis is the causative agent of tuberculosis in domestic and wild animal species and sometimes in humans, presenting variable degrees of pathogenicity. It is known that PknG is involved in the first steps of Mycobacterium tuberculosis macrophage infection and immune evasion. We questioned whether M. bovispknG genes were conserved among mycobacteria and if natural genetic modifications would affect its virulence. We discovered a single mutation at a catalytic domain (R242P) of one M. bovis isolate and established the relation between the presence of R242P mutation and enhanced M. bovis virulence. Here, we demonstrated that R242P mutation alters the PknG protein conformation to a more open ATP binding site cleft. It was observed that M. bovis with PknG mutation resulted in increased growth under stress conditions. In addition, infected macrophages by M. bovis (R242P) presented a higher bacterial load compared with M. bovis without the pknG mutation. Furthermore, using the mouse model of infection, animals infected with M. bovis (R242P) had a massive innate immune response migration to the lung that culminated with pneumonia, necrosis, and higher mortality. The PknG protein single point mutation in its catalytic domain did not reduce the bacterial fitness but rather increased its virulence.

Serine proteases in neutrophil extracellular traps exhibit anti-Respiratory Syncytial Virus activity.

Human respiratory syncytial virus (hRSV) is an infectious agent in infants and young children which there are no vaccines or drugs for treatment. Neutrophils are recruited for airway, where they are stimulated by hRSV to release large amounts of neutrophil extracellular traps (NETs). NETs are compound by DNA and proteins, including microbicidal enzymes. They constitute a large part of the mucus accumulated in the lung of patients, compromising their breathing capacity. In contrast, NETs can capture/inactivate hRSV, but the molecules responsible for this effect are unknown. OBJECTIVES: We selected microbicidal NET enzymes (elastase, myeloperoxidase, cathepsin-G, and proteinase-3) to assess their anti-hRSV role. METHODS AND RESULTS: Through in vitro assays using HEp-2 cells, we observed that elastase, proteinase-3, and cathepsin-G, but not myeloperoxidase, showed virucidal effects even at non-cytotoxic concentrations. Elastase and proteinase-3, but not cathepsin-G, cleaved viral F-protein, which is responsible for viral adhesion and fusion with the target cells. Molecular docking analysis indicated the interaction of these macromolecules in the antigenic regions of F-protein through the active regions of the enzymes. CONCLUSIONS: Serine proteases from NETs interact and inactive hRSV. These results contribute to the understanding the role of NETs in hRSV infection and to designing treatment strategies for the inflammatory process during respiratory infections.

Rocio Virus: An Updated View on an Elusive Flavivirus.

Rocio virus (ROCV) is a mosquito-borne flavivirus and human pathogen. The virus is indigenous to Brazil and was first detected in 1975 in the Sao Paulo State, and over a period of two years was responsible for several epidemics of meningoencephalitis in coastal communities leading to over 100 deaths. The vast majority of ROCV infections are believed to be subclinical and clinical manifestations can range from uncomplicated fever to fatal meningoencephalitis. Birds are the natural reservoir and amplification hosts and ROCV is maintained in nature in a mosquito-bird-mosquito transmission cycle, primarily involving Psorophora ferox mosquitoes. While ROCV has remained mostly undetected since 1976, in 2011 it re-emerged in Goiás State causing a limited outbreak. Control of ROCV outbreaks depends on sustainable vector control measures and public education. To date there is no specific treatment or licensed vaccine available. Here we provide an overview of the ecology, transmission cycles, epidemiology, pathogenesis, and treatment options, aiming to improve our ability to understand, predict, and ideally avert further ROCV emergence.

Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1).

Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19. Communicated by Ramaswamy H. Sarma.

Dynamic behavior of Dengue and Zika viruses NS1 protein reveals monomer-monomer interaction mechanisms and insights to rational drug design.

Communicated by Ramaswamy H. Sarma.