Hantaviruses are single-stranded RNA viruses belonging to the family Bunyaviridae that causes hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) worldwide. Currently, there is no effective vaccination or therapy available for the treatment of hantavirus, hence there is a dire need for research to formulate therapeutics for the disease. Computational vaccine designing is currently a highly accurate, time and cost-effective approach for designing effective vaccines against different diseases. In the current study, we shortlisted highly antigenic proteins i.e., envelope, and nucleoprotein from the proteome of hantavirus and subjected to the selection of highly antigenic epitopes to design of next-generation multi-epitope vaccine constructs. A highly antigenic and stable adjuvant was attached to the immune epitopes (T-cell, B-cell, and HTL) to design Env-Vac, NP-Vac, and Com-Vac constructs, which exhibit stronger antigenic, non-allergenic, and favorable physiochemical properties. Moreover, the 3D structures were predicted and docking analysis revealed robust interactions with the human Toll-like receptor 3 (TLR3) to initiate the immune cascade. The total free energy calculated for Env-Vac, NP-Vac, and Com-Vac was -50.02 kcal/mol, -24.13 kcal/mol, and -62.30 kcal/mol, respectively. In silico cloning, results demonstrated a CAI value for the Env-Vac, NP-Vac, and Com-Vac of 0.957, 0.954, and 0.956, respectively, while their corresponding GC contents were 65.1%, 64.0%, and 63.6%. In addition, the immune simulation results from three doses of shots released significant levels of IgG, IgM, interleukins, and cytokines, as well as antigen clearance over time, after receiving the vaccine and two booster doses. Our vaccines against Hantavirus were found to be highly immunogenic, inducing a robust immune response that demands experimental validation for clinical usage.

Hypoxia-inducible factors (HIFs) are transcription factors that regulate erythropoietin (EPO) synthesis and red blood cell (RBC) production. Prolyl-4-hydroxylase domain (PHD) enzymes are key regulators of HIF’s stability and activity. Inhibiting PHD enzymes can enhance HIF-mediated responses and have therapeutic potential for diseases such as anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation. In this study, we searched for novel PHD inhibitors from four databases of natural products and synthetic compounds: AfroDb Natural Products, AnalytiCon Discovery Natural Product (NP), HIM-Herbal Ingredients In-Vivo Metabolism, and Herbal Ingredients’ Targets, with a total number of 13,597 compounds. We screened the candidate compounds by molecular docking and validated them by molecular dynamics simulations and free energy calculations. We identified four target hits (ZINC36378940, ZINC2005305, ZINC31164438, and ZINC67910437) that showed stronger binding affinity to PHD2 compared to the positive control, Vadadustat (AKB-6548), with docking scores of − 13.34 kcal/mol, − 12.76 kcal/mol, − 11.96 kcal/mol, − 11.41 kcal/mol, and − 9.04 kcal/mol, respectively. The target ligands chelated the active site iron and interacted with key residues (Arg 383, Tyr329, Tyr303) of PHD2, in a similar manner as Vadadustat. Moreover, the dynamic stability-based assessment revealed that they also exhibited stable dynamics and compact trajectories. Then the total binding free energy was calculated for each complex which revealed that the control has a TBE of − 31.26 ± 0.30 kcal/mol, ZINC36378940 reported a TBE of − 38.65 ± 0.51 kcal/mol, for the ZINC31164438 the TBE was − 26.16 ± 0.30 kcal/mol while the ZINC2005305 complex reported electrostatic energy of − 32.75 ± 0.58 kcal/mol. This shows that ZINC36378940 is the best hit than the other and therefore further investigation should be performed for the clinical usage. Our results suggest that these target hits are promising candidates that reserve further in vitro and in vivo validations as potential PHD inhibitors for the treatment of renal anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation.

Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus's NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus's evasion of the immune response. In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25. The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski's rule. Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition of the terminal hair follicle, which can present in sporadic, familial, or syndromic forms. The exact pathogenesis of HS remains elusive, posing a challenge for the development of effective treatments. Among the various immunological mechanisms, the NLRP3 inflammasome is thought to contribute to the pathogenesis of HS, releasing cytokines such as IL-1β and IL-18 which initiates and exacerbates inflammation. Consequently, targeting NLRP3 offers a potential strategy for mitigating inflammation in HS-affected skin. In this study we used the docking, molecular dynamics simulation and binding free energy approaches to identify the potent inhibitor of NLRP3 by screening the African phytocompounds and traditional Chinese medicine databases. Our virtual drug screening analysis identified two lead compounds from each database, characterized by high docking scores such as SA-21676268 (-8.135 kcal/mol), SA-167673 (-10.251 kcal/mol), EA-45360194 (-10.376 kcal/mol), EA-46881231 (-10.011 kcal/mol), NEA-44258150 (-9.856 kcal/mol), NEA-135926572 (-7.662 kcal/mol), NA-163089376 (-9.237 kcal/mol), NA-440735 (-8.826 kcal/mol), TCM-392442 (-10.438 kcal/mol), and TCM-10043097 (-9.046 kcal/mol) which highlighted the strong binding affinity as compared to the control NP3-146 drug (-5.09 kcal/mol). Moreover, the values of dissociation constant further validated the strong binding affinity between the identified lead compounds and NLRP3. The dynamic stability and strong bonding energies of the lead compounds-NLRP3 complexes were confirmed by the molecular dynamic simulation and binding free energy calculation. The analysis of ADMET properties for all compounds indicated high intestinal absorption, water solubility, absence of hepatotoxicity, and skin sensitivity. In conclusion, our molecular simulations and binding free energy calculations confirmed the strong affinity of these lead compounds for NLRP3 as compared to the control drug, highlighting their potential as part of a combinatorial therapeutic strategy for HS to effectively reduce disease-related inflammation.

A direct and highly regioselective method for synthesizing 2,6-diiodophenylethanol is presented. In silico analysis shows compounds 7a, 7p, 7t, and 7z interact favourably with IDO/TDO receptors, highlighting their unmatched anticancer potential.

Diabetes mellitus is prevalent worldwide, with vascular complications responsible for over 70% of deaths associated with the condition. Methylglyoxal (MGO), a by-product of glycolysis, is a significant modulator of vascular dysfunction in diabetes. Sestrin2 (SESN2) has been recognized as a vital regulator of cellular homeostasis and stress responses. Although SESN2’s role in cellular defense is gaining recognition, its precise function in endothelial cells under diabetic-like conditions remains poorly understood. This study examines the role of SESN2 in preserving endothelial cell angiogenic function under MGO-induced stress. The study reveals that SESN2 is a vital regulator of multiple protective pathways, as demonstrated by both loss-of-function and gain-of-function approaches in EA.hy926 endothelial cells. Our data showed that SESN2 overexpression significantly maintained tubular network formation, proliferation, and invasive capacity under MGO stress, whereas SESN2 silencing exacerbated MGO-induced impairment of angiogenic capacity. SESN2 was identified as orchestrating NRF2/HO-1 antioxidant pathway activation while simultaneously enhancing VEGF-C expression, offering a dual strategy for cellular protection and angiogenesis. Moreover, SESN2 facilitated a regulated equilibrium of the AKT/mTOR signaling pathway, ensuring synchronized activation during stress conditions. SESN2 also regulated stress-activated MAPK pathways, diminishing P38 and ERK1/2 activation upon MGO exposure. This study highlights SESN2 as a pivotal regulator of endothelial cell homeostasis and angiogenic activity under MGO-induced stress, indicating its potential as a therapeutic target for addressing diabetic vascular complications and improving patient outcomes.