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Schistosomiasis, a neglected tropical disease caused by flatworms of the Schistosoma genus, can lead to severe health complications such as Hepatosplenomegaly, intestinal cancer, anemia, and heightened susceptibility to other infections like HIV. With limited treatment options, especially given the potential rise of drug resistance to the sole available drug, Praziquantel (PZQ), there is an imperative to discover novel and effective drugs against Schistosomiasis. In regards, a computational molecular modelling strategy was employed, with a specific focus on Schistosoma mansoni Thioredoxin glutathione reductase (SmTGR). Using structure-based drug design, we searched the ChEMBL database for lead compounds, identifying Compound 34 with a remarkable binding score of −167.014 kcal mol−1. Six new potent compounds were designed with enhanced binding (−169.451 to −181.579 kcal mol−1) and predicted activities (6.082–6.765) compared to both the lead compound and the standard drug, PZQ. Rigorous validation through molecular dynamics (MD) simulations confirmed the stability and integrity of the docked complexes. An evaluation of drug-likeness and ADMET characteristics revealed that the newly developed analogues possess favourable pharmacokinetic profiles, adhering to Lipinski's rule of five. In addition, the synergistic insights gained from density functional theory (DFT) analyses further underscore the structural diversity and potential applications of these derivatives. [ABSTRACT FROM AUTHOR]

Schistosomiasis, also known as bilharzia or snail fever, is a tropical parasitic disease resulting from flatworms of the Schistosoma genus. This often overlooked disease has significant impacts in affected regions, causing enduring morbidity, hindering child development, reducing productivity, and creating economic burdens. Praziquantel (PZQ) is currently the only treatment option for schistosomiasis. Given the potential rise of drug resistance and the limited treatment choices available, there is a need to develop more effective inhibitors for this neglected tropical disease (NTD). In view of this, quantitative structure-activity relationship studies (QSAR), molecular docking, molecular dynamics simulations, drug-likeness, and ADMET predictions were applied to 31 inhibitors of Schistosoma mansoni Dihydroorotate dehydrogenase (SmDHODH). The designed QSAR model demonstrated robust statistical parameters including an R2 of 0.911, R2adj of 0.890, Q2cv of 0.686, R2pred of 0.807, and cR2p of 0.825, confirming its robustness. Compound 26, identified as the most active derivative, emerged as a lead candidate for new potential inhibitors through ligand-based drug design. Subsequently, 12 novel compounds (26A-26L) were designed with enhanced inhibition activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding and hydrophobic interactions, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules (26A and 26L). Furthermore, drug-likeness and ADMET prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for treating schistosomiasis. Author summary: In an innovative effort to combat schistosomiasis, we have employed a computational drug innovation approach to design a potential treatment options. Schistosomiasis, a parasitic disease affecting millions worldwide, has been a persistent global health challenge. The study, nestled within the broader realm of life sciences, sought to identify a more effective drug using computational methods that analyze highly effective derivatives targeting SmDHODH. This pioneering approach not only accelerates the drug discovery process but also offers a promising avenue for developing targeted treatments. By harnessing computational power, we systematically explored chemical databases to pinpoint compounds with the potential to combat schistosomiasis. The findings hold significant implications for both scientists and non-scientists, as they represent a step forward in addressing a major public health concern. For scientists, this work exemplifies the integration of in silico techniques in drug development, while non-scientists can appreciate the tangible impact on improving global health and the well-being of communities affected by schistosomiasis. This research underscores the power of interdisciplinary efforts in advancing our ability to tackle complex health challenges. [ABSTRACT FROM AUTHOR]

Influenza virus transmission is largely mediated by its mutation and genome reassortment from distinct strains resulting in drug-resistances and pandemics. This necessitates the need for the discovery of more potential influenza inhibitors to prevent future epidemics. An in-silico approach was utilized here to design six new (21a-f) potential inhibitors of influenza neuraminidase (NA) using a hit compound 21 with good binding affinity, pre- dicted activity, and pharmacokinetic properties in our previous work. The modeled activities (pEC50) of the newly designed compounds (ranging between 8.188 and 7.600) were better than that of the hit compound 21 with predicted activity (pEC50) of 6.0101 and zanamivir (pEC50 of 5.6755) as the standard reference control used. The MolDock scores (ranging between-189.67 and 142.47 kcal/mol) of these newly designed compounds in the NA binding cavity were also better than the hit template 21 with a MolDock score of-125.33 kcal/mol and zanamivir standard drug (-136.36 kcal/mol). In addition, the conformational stability of the best-designed compound 21a in the NA binding cavity was further studied through the MD simulation of 100 ns. Moreover, the drug-likeness and ADMET predictions of these designed compounds showed their good oral bioavailability and pharmacokinetic profiling respectively. More so, the DFT calculations also revealed the relevance of these designed com- pounds in view of their smaller band energy gaps from the frontier molecular orbital calculations. This study could serve as a reliable in-silico perspective for the search and discovery of potential anti-influenza agents. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis. [ABSTRACT FROM AUTHOR]