Tepotinib and tivantinib as potential inhibitors for the serine/threonine kinase of the mpox virus: insights from structural bioinformatics analysis.

The serine/threonine kinase (STK) plays a central role as the primary kinase in poxviruses, directing phosphoryl transfer reactions. Such reactions are pivotal for the activation of certain proteins during viral replication, assembly, and maturation. Therefore, targeting this key protein is anticipated to impede virus replication. In this work, a structural bioinformatics approach was employed to evaluate the potential of drug-like kinase inhibitors in binding to the ATP-binding pocket on the STK of the Mpox virus. Virtual screening of known kinase inhibitors revealed that the top 10 inhibitors exhibited binding affinities ranging from -8.59 to -12.05 kcal/mol. The rescoring of compounds using the deep-learning default model in GNINA was performed to predict accurate binding poses. Subsequently, the top three inhibitors underwent unbiased molecular dynamics (MD) simulations for 100 ns. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and Principal Component Analysis (PCA) suggested tepotinib as a competitive inhibitor for Mpox virus STK as evidenced by its binding free energy and the induction of similar conformational behavior of the enzyme. Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.Communicated by Ramaswamy H. Sarma.

Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.

Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.

How helpful were molecular dynamics simulations in shaping our understanding of SARS-CoV-2 spike protein dynamics?

The SARS-CoV-2 spike protein (S) represents an important viral component that is required for successful viral infection in humans owing to its essential role in recognition of and entry to host cells. The spike is also an appealing target for drug designers who develop vaccines and antivirals. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. MD simulations found that the higher affinity of SARS-CoV-2-S to ACE2 is linked to its unique residues that add extra electrostatic and van der Waal interactions in comparison to the SARS-CoV S. This illustrates the spread potential of the pandemic SARS-CoV-2 relative to the epidemic SARS-CoV. Different mutations at the S-ACE2 interface, which is believed to increase the transmission of the new variants, affected the behavior and binding interactions in different simulations. The contributions of glycans to the opening of S were revealed via simulations. The immune evasion of S was linked to the spatial distribution of glycans. This help the virus to escape the immune system recognition. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. This will pave the way to us preparing for the next pandemic as the computational tools are tailored to help fight new challenges.

Effect of the molar ratio of (Ni2+ and Fe3+) on the magnetic, optical and antibacterial properties of ternary metal oxide CdO-NiO-Fe2O3 nanocomposites.

In this work, the effect of the molar ratio of (Ni2+ and Fe3+) on the properties of CdO-NiO-Fe2O3 nanocomposites was investigated. The synthesis of CdO-NiO-Fe2O3 nanocomposites was carried out by self-combustion. XRD, UV-Vis, PL and VSM were used to describe the physical properties of the materials. The results showed significant progress in structural and optical properties supporting antibacterial activity. For all samples, the particle size decreased from 28.96 to 24.95 nm with increasing Ni2+ content and decreasing Fe3+ content, as shown by the XRD pattern, which also shows the crystal structure of cubic CdO, cubic NiO, and cubic γ-Fe2O3 spinel. The Ni2+ and Fe3+ contents in the CdO-NiO-Fe2O3 nanocomposites have also been shown to enhance the ferromagnetic properties. Due to the significant coupling between Fe2O3 and NiO, the coercivity Hc values of the samples increase from 66.4 to 266 Oe. The potential of the nanocomposites for antibacterial activity was investigated against Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Escherichia coli, and Moraxella catarrhalis) bacteria. Comparison of P. aeruginosa with E. coli, S. aureus and M. catarrhalis showed that it has a stronger antibacterial activity with a ZOI of 25 mm.

Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico.

BACKGROUND: Last year, the human monkeypox virus (hMPXV) emerged as an alarming threat to the community, with a detectable outbreak outside the African continent for the first time. According to The American Centers for Disease Control and Prevention (CDC), the virus is reported globally, with 86,746 confirmed cases (until April 08, 2023). DNA-dependent RNA polymerase (DdRp) is an essential protein for viral replication; hence it is a promising drug target for developing antiviral drugs against DNA viruses. Therefore, this study was conducted to search for natural compounds that could provide scaffolds for RNA polymerase inhibitors. METHODS: In this study, the DdRp structure of hMPXV was modeled and used to screen the natural compounds database (COCONUT). The virtual screening revealed 15 compounds able to tightly bind to the active site of the DdRp (binding energies less than -7.0 kcal/mol) compared to the physiological nucleotide, guanosine triphosphate (GTP). Molecular dynamics simulation was then performed on the top four hits and compared to GTP RESULTS: The results revealed the potential of four compounds (comp289, comp295, comp441, and comp449) in binding the hMPXV DdRp active site with a comparable binding affinity (-17.06 ± 2.96, -11.6 ± 5.34, -14.85 ± 2.66, and -10.79 ± 4.49 kcal/mol) with GTP (-21.03 ± 7.55 kcal/mol) CONCLUSION: These findings may also pave the way for developing new hMPXV inhibitors based on natural product scaffolds. These results need further experimental validation but promising as it was validated by unbiased all-atom MD simulations and binding free energy calculations.

The discovery of novel antivirals for the treatment of mpox: is drug repurposing the answer?

INTRODUCTION: Drugs that have demonstrated good activity against any member of the Orthopoxvirus genus are good candidates for repurposing studies against the mpox virus (MPXV). The conserved biology of poxviruses has proven beneficial from a clinical virology perspective. Evolutionarily conserved proteins tend to function in a highly similar way. Indeed, the smallpox vaccine was found to be 85% effective in protecting humans from mpox virus infection. Similarly, tecovirimat, the drug of choice for smallpox infections, was recently repurposed as a treatment option for mpox cases in Europe. AREA COVERED: This review article focuses on drug repurposing strategies to combat the newly emerged MPXV outbreak. The viral and host cell protein targets are challenged with a bunch of drugs and drug-like molecules in silico, in vitro, and in vivo. Some drugs show promising results and can be repurposed to eradicate MPXV infection. The authors also highlight potential limitations and provide their expert perspectives. EXPERT OPINION: Overall, it is clear that we cannot solely rely on the conventional drug discovery pipeline to find new treatments, despite advances in computational and experimental advances in the last few decades. Drug repurposing has successfully identified good candidate drugs against MPXV as it is one of the Orthopoxvirus genus family. Tecovirimat, brincidofovir, and cidofovir have shown promising results in preventing virus propagation. Consequently, drug repurposing represents an important strategy for the fast identification of new therapeutic options.

Computational identification of drug-like marine natural products as potential RNA polymerase inhibitors against Nipah virus.

Nipah virus (NiV) has been an alarming threat to human populations in southern Asia for more than a decade. It is one of the most deadly viruses in the Mononegavirales order. Despite its high mortality rate and virulence, no chemotherapeutic agent or vaccine is publicly available. Hence, this work was conducted to computationally screen marine natural products database for drug-like potential inhibitors for the viral RNA-dependent RNA polymerase (RdRp). The structural model was subjected to molecular dynamics (MD) simulation to obtain the native ensemble of the protein. The CMNPDB dataset of marine natural products was filtered to retain only compounds following Lipinski's five rules. The molecules were energy minimized and docked into different conformers of the RdRp using AutoDock Vina. The best 35 molecules were rescored by GNINA, a deep learning-based docking software. The resulting nine compounds were evaluated for their pharmacokinetic profiles and medicinal chemistry properties. The best five compounds were subjected to MD simulation for 100 ns, followed by binding free energy estimation via Molecular Mechanics/ Generalized Born Surface Area (MM/GBSA) calculations. The results showed remarkable behavior of five hits as inferred by stable binding pose and orientation to block the exit channel of RNA synthesis products in the RdRp cavity. These hits are promising starting materials for in vitro validation and structural modifications to enhance the pharmacokinetic and medicinal chemistry properties for developing antiviral lead compounds.

In silico structural elucidation of Nipah virus L protein and targeting RNA-dependent RNA polymerase domain by nucleoside analogs.

The large (L) protein of Mononegavirales is a multi-domain protein that performs transcription and genome replication. One of the important domains in L is the RNA-dependent RNA polymerase (RdRp), a promising target for antiviral drugs. In this work, we employed rigorous computational comparative modeling to predict the structure of L protein of Nipah virus (NiV). The RdRp domain was targeted by a panel of nucleotide analogs, previously reported to inhibit different viral RNA polymerases, using molecular docking. Best binder compounds were subjected to molecular dynamics simulation to validate their binding. Molecular mechanics/generalized-born surface area (MM/GBSA) calculations estimated the binding free energy. The predicted model of NiV L has an excellent quality as judged by physics- and knowledge-based validation tests. Galidesivir, AT-9010 and Norov-29 scored the top nucleotide analogs to bind to the RdRp. Their binding free energies obtained by MM/GBSA (-31.01 ± 3.9 to -38.37 ± 4.8 kcal/mol) ranked Norov-29 as the best potential inhibitor. Purine nucleotide analogs are expected to harbor the scaffold for an effective drug against NiV. Finally, this study is expected to provide a start point for medicinal chemistry and drug discovery campaigns toward identification of effective chemotherapeutic agent(s) against NiV.Communicated by Ramaswamy H. Sarma.

Molecular pathogenesis of dengue virus infection in Aedes mosquitoes.

Aedes mosquitoes are implicated in the transmission of several viruses, including Dengue virus (DENV) to millions of people worldwide. The global expansion of Aedes mosquitos'habitats creates a desperate need for control mechanisms with minimum negative effects. Deciphering the molecular interactions between DENV and its vector is a promising field to develop such efficient control strategies. As soon as the viremic blood is ingested by the mosquito, DENV is encountered by different innate immunity responses. During the past three decades, different pathways of innate immunity have been identified in Aedes spp. Recognition of viral molecular patterns, including viral RNA, and vector attempts to resist DENV infection are the most important defense mechanisms. Crosstalk between innate immune pathways and redundancy of anti-DENV responses become more evident as research progresses. The viral evasion and repression of vector immune response are increasingly being discovered. Such viral strategies are potential targets to be disrupted in order to limit DENV infection and spread. Vector-related non-immune factors such as gut microbiota can also be tapped for efficient control of DENV infection in Aedes mosquito's populations without affecting their fitness. Current trends in controlling DENV in its vector are exploring the potentials of using genetically engineered mosquitoes via RNA-based systems to degrade DENV genome once released into the midgut cells cytoplasm at the early phase of the infection.

Bacterial riboswitches and RNA thermometers: Nature and contributions to pathogenesis.

Bacterial pathogens are always challenged by fluctuations of chemical and physical parameters that pose serious threats to cellular integrity and metabolic status. Sudden deprivation of nutrients or key metabolites, changes in surrounding pH, and temperature shifts are the most important examples of such parameters. To elicit a proper response to such fluctuations, bacterial cells coordinate the expression of parameter-relevant genes. Although protein-mediated control of gene expression is well appreciated since many decades, RNA-based regulation has been discovered in early 2000s as a parallel level of regulation. Small regulatory RNAs have emerged as one of the most widespread and important gene regulatory systems in bacteria with rare representatives found in Archaea and Eukarya. Riboswitches and thermosensors are cis-encoded RNA regulatory elements that employ different mechanisms to regulate the expression of related genes controlling key metabolic pathways and genes of temperature relevant proteins including virulence factors. The extent of RNA contributions to gene regulation is not completely known even in well-studied models such E. coli and B. subtilis. In depth understanding of riboswitches is promising for opportunity to discover a narrow spectrum antibacterial drugs that target riboswitches of essential metabolic pathways.