Schistosomiasis is a neglected tropical disease caused by Schistosoma sp., and praziquantel (PZQ) is the first-line treatment. However, traditional PZQ formulations have low solubility and fast metabolism, limiting its effectiveness. Thus, nanoparticles have been proposed to improve the bioavailability and efficacy of poorly soluble antischistosomal drugs.

This systematic review used in vivo preclinical studies to map the available evidence and compare the efficacy of free PZQ and PZQ-based nanostructured formulations (N-PZQ) for schistosomiasis treatment.

PubMed, Embase, Scopus, and Web of Science were searched, and 1186 experimental studies published between 1974 and 2024 were screened. Parasitological, histopathological, pharmacokinetic, and toxicological outcomes were evaluated.

Twelve relevant studies were identified exploring N-PZQ formulations based on liposomes, nanoliposomes, and nanocrystals. N-PZQ demonstrated better therapeutic efficacy than free PZQ, reducing parasite load, modifying oogram profiles, and down-regulating liver granuloma development (number and size). N-PZQ also exhibited improved pharmacokinetic profile, with enhanced bioavailability and longer half-life, as well as reduced toxicity (cytotoxicity, genotoxicity, and hepatotoxicity) compared to free PZQ.

PZQ-based nanostructured formulations represent a promising strategy to enhance schistosomiasis treatment by improving chemotherapy efficacy, optimizing antiparasitic responses, pharmacokinetics, and reducing drug toxicity.

As a leading contender in the study of luminescence, nanoluciferase has recently attracted attention and proven effective in a wide variety of research areas. Although numerous attempts have been made to improve activity, there has yet to be a thorough exploration of further possibilities to improve thermostability. In this study, protein engineering in tandem with molecular dynamics simulation at various temperatures (300 K, 400 K, 450 K and 500 K) was used to improve our understanding of nanoluciferase dynamics and identification of factors that could significantly enhance the thermostability. Based on these, three novel mutations have been narrowed down, which were hypothesised to improve thermostability. Root mean square deviation and root mean square fluctuation studies confirmed higher stability of mutant at high temperature. Solvent-accessible surface area and protein unfolding studies revealed a decreased tendency of mutant to unfold at higher temperatures. Further free energy landscape and principal component analysis was adapted to get deeper insights into the thermodynamic and structural behavior of these proteins at elevated temperature. Thus, this study provides a deeper insight into the dynamic factors for thermostability and introduces a novel, enhanced nanoluciferase candidate with potential use in industry.

At the beginning of the last century, multiple pandemics caused by influenza (flu) viruses severely impacted public health. Despite the development of vaccinations and antiviral medications to prevent and control impending flu outbreaks, unforeseen novel strains and continuously evolving old strains continue to represent a serious threat to human life. Therefore, the recently identified H10N7, for which not much data is available for rational structure-based drug design, needs to be further explored. Here, we investigated the structural dynamics of neuraminidase N7 upon binding of inhibitors, and the drug resistance mechanisms against the oseltamivir (OTV) and laninamivir (LNV) antivirals due to the crucial R292K mutation on the N7 using the computational microscope, molecular dynamics (MD) simulations. In this study, each system underwent long 2 × 1 μs MD simulations to answer the conformational changes and drug resistance mechanisms. These long time-scale dynamics simulations and free energy landscapes demonstrated that the mutant systems showed a high degree of conformational variation compared to their wildtype (WT) counterparts, and the LNV-bound mutant exhibited an extended 150-loop conformation. Further, the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculation and MM/GBSA free energy decomposition were used to characterize the binding of OTV and LNV with WT, and R292K mutated N7, revealing the R292K mutation as drug-resistant, facilitated by a decline in binding interaction and a reduction in the dehydration penalty. Due to the broader binding pocket cavity of the smaller K292 mutant residue relative to the wildtype, the drug carboxylate to K292 hydrogen bonding was lost, and the area surrounding the K292 residue was more accessible to water molecules. This implies that drug resistance could be reduced by strengthening the hydrogen bond contacts between N7 inhibitors and altered N7, creating inhibitors that can form a hydrogen bond to the mutant K292, or preserving the closed cavity conformations.

Gastric cancer (GC) is the fifth most prevalent form of cancer worldwide. CagA - positive Helicobacter pylori infects more than 60% of the human population. Moreover, chronic infection of CagA-positive H. pylori can directly affect GC incidence. In the current study, we have repurposed FDA-approved antibiotics that are viable alternatives to current regimens and can potentially be used as combination therapy against the CagA of H. pylori. The 100 FDA-approved gram negative antibiotics were screened against CagA protein using the AutoDock 4.2 tool. Further, top nine compounds were selected based on higher binding affinity with CagA. The trajectory analysis of MD simulations reflected that binding of these drugs with CagA stabilizes the system. Nonetheless, atomic density map and principal component analysis also support the notion of stable binding of antibiotics to the protein. The residues ASP96, GLN100, PRO184, and THR185 of compound cefpiramide, doxycycline, delafloxacin, metacycline, oxytetracycline, and ertapenem were involved in the binding with CagA protein. These residues are crucial for the CagA that aids in entry or pathogenesis of the bacterium. The screened FDA-approved antibiotics have a potential druggability to inhibit CagA and reduce the progression of H. pylori borne diseases.

The Janus kinase (JAK) is a master regulator of the JAK/STAT pathway. Dysregulation of this signalling cascade causes neuroinflammation and autoimmune disorders. Therefore, JAKs have been characterized as an attractive target for developing anti-inflammatory drugs. Nowadays, designing efficient, effective, and specific targeted therapeutics without being cytotoxic has gained interest. We performed the virtual screening of natural products in combination with pharmacological analyses. Subsequently, we performed molecular dynamics simulations to study the stability of the ligand-bound complexes and ligand-induced inactive conformations. Notably, inactive kinases display remarkable conformational plasticity; however, ligand-induced molecular mechanisms of these conformations are still poorly understood. Herein, we performed a free energy landscape analysis to explore the conformational plasticity of the JAK1 kinase. Leonurine, STOCK1N-68642, STOCK1N-82656, and STOCK1N-85809 bound JAK1 exhibited a smooth transition from an active (αC-in) to a completely inactive conformation (αC-out). Ligand binding induces disorders in the αC-helix. Molecular mechanics Poisson Boltzmann surface area (MM/PBSA) calculation suggested three phytochemicals, namely STOCK1N-68642, Epicatechin, and STOCK1N-98615, have higher binding affinity compared to other ligand molecules. The ligand-induced conformational plasticity revealed by our simulations differs significantly from the available crystal structures, which might help in designing allosteric drugs.

Although primary infection of Epstein-Barr virus is generally non-lethal, viral reactivation is often associated with fatal outcomes. Regardless, there is no FDA-approved treatment available for this viral infection. The current investigation targets viral maintenance and reactivation by inhibiting the functioning of viral deoxyuridine-triphosphatase (dUTPase) using phytochemicals. The EBV-dUTPase is essential for the maintenance of nucleotide balance and thus, plays a vital role in the viral replication cycle. Additionally, the protein has shown neuroinflammatory effects on the host. To selectively target the protein and possibly alter its activity, we utilized a virtual screening approach and screened 45 phytochemicals reported to have antiviral, anti-inflammatory, and neuroprotective properties. The analysis revealed several phytochemicals bound to the target protein with high affinity. In-silico ADMET and Lipinski's rule analysis predicted favorable druggability of Dehydroevodiamine (DHE) among all the phytochemicals. Further, we corroborated our findings by molecular dynamic simulation and binding affinity estimation. Our outcomes ascertained a stable binding of DHE to EBV-dUTPase primarily through electrostatic interactions. We identified that the protein-ligand binding involves the region around His71, previously reported as a potent drug target site. Conclusively, the phytochemical DHE showed a promising future as a drug development candidate against EBV-dUTPase.

The dysfunction of the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway results in several pathophysiological conditions, including autoimmune disorders. The negative feedback regulators of the JAK/STAT signaling pathway, suppressors of cytokine signaling (SOCS), act as a natural inhibitor of JAK and inhibit aberrant activity. SOCS1 is the most potent member of the SOCS family, whose kinase inhibitory region targets the substrate-binding groove of JAK with high affinity and blocks the phosphorylation of JAK kinases. Overall, we performed an aggregate of 13 μs molecular dynamics simulations on the activation loop's three different phosphorylation (double and single) states. Results from our simulations show that the single Tyr¹⁰³⁴ phosphorylation could stabilize the JAK1/SOCS1 complex as well as the flexible activation segment. The phosphate-binding loop (P-loop) shows conformational variability at dual and single phosphorylated states. Principal component analysis and protein structure network (PSN) analysis reveal that the different phosphorylation states and SOCS1 binding induce intermediate inactive conformations of JAK1, which could be a better target for future JAK1 selective drug design. PSN analysis suggests that the com-pY1034 system is stabilized due to higher values of network hubs than the other two complex systems. Moreover, the binding free energy calculations suggest that pTyr¹⁰³⁴ states show a higher affinity toward SOCS1 than the dual and pTyr¹⁰³⁵ states. We believe that the mechanistic understanding of JAK1/SOCS1 complexation will aid future studies related to peptide inhibitors based on SOCS1.