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Although these phytochemicals compounds were also screened in our study, they displayed limited interaction with both site ?- and II-targeted epitopes [67]


Mar 3, 2022

Although these phytochemicals compounds were also screened in our study, they displayed limited interaction with both site ?- and II-targeted epitopes [67]. bench G6PD activator AG1 CLC Drug Discovery. We also performed Quantitative Structure-Activity and Relationship (QSAR) for the lead best binders known for their antiviral activity. Among one million tested ligands, seven ligands (PubChem ID: 3714418, 24787350, 49828911, 24802036, 79824892, 49726463, and 3139884) were identified as the best binders to neutralizing epitopes site ? and four ligands (PubChem ID: 865999, 17505357, 24802036, and 24285058) to neutralizing epitopes site II, respectively. These binders exhibited significant interactions with neutralizing epitopes on RSV F, with an average of six H bonds, docking energy of ? 15.43 Kcalmol?1, and minimum interaction energy of ? 7.45 Kcalmol?1. Using in silico virtual screening, we identified potential RSV inhibitors that bind two major antigenic sites on the RSV F protein. Using structure-based design and combination-based drug therapy, identified molecules could be modified to generate the next generation anti-RSV drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s42247-021-00213-6. value of the lead binders ranged from 0.25 to 5.99 log units. This value was observed higher for all the lead compounds except for compound K, which had a log value less than 1.00 log unit. Predicted properties for the best binders to site ? and site II for various models are summarized in supplementary information Table S1 and Table S2. Discussion RSV is still Rabbit Polyclonal to MBD3 the leading cause of lower respiratory tract disease in infants, to which neither vaccines nor treatments are available [47]. Further, RSV affects all G6PD activator AG1 age groups [48] and causes repeated infections without significant changes in the antigenic sites [49, 50]. Therefore, there is a significant need to determine or develop efficacious therapeutics, including novel small molecules, to control RSV infections. The fusion (F) protein is a class I fusion glycoprotein and has been identified as a major target for antiviral medicines and vaccine development [49, 51]. Until recently, the development of an efficient vaccine has been hurdled from the limited understanding of G6PD activator AG1 the conformational rearrangement between metastable pre-F and stable post-F [52, 53]. Nonetheless, solving the crystal structural of the pre-F protein revealed major neutralizing epitopes, additional to those present in the post-F conformation [20]. Among these, site ? represents the major target for neutralizing antibodies, accounting for 35% and 47% of the overall response in RSV-A and RSV-B, respectively [19]. Additionally, site II is present on both conformations and G6PD activator AG1 is the target for the traditionally prophylactic antibody palivizumab [20, 54]. However, there are several limitations in using palivizumab [55]. For example, it is recommended to only treat premature infected infants, but it is not advised to treat those with congenital heart disease and additional selected populations [54]. On the other hand, the recently structurally defined antigenic site ? on pre-F has a neutralization potency 10- to 100-collapse greater than palivizumab [38]. Considering all the above, we designed this in silico analysis to display for inhibitors that can interfere with both sites and could be potentially tested as antiviral medicines in the future. To do so, we used a similar approach to what we have recently reported with influenza [56] and ran a high-throughput computational screening of one million selected by using the CLC Drug Discovery Workbench. Firstly, compounds that showed no interaction with the active sites in site ? and site II in the initial screening were excluded. Secondly, compounds that created at least six HB with a minimum quantity of IE and DS were selected as the best binders. Using this method, we selected the ten best poses for each conformation of the best docking energy (DE) based on rating functions [57]. Using these criteria, we recognized seven and four hit candidates that target RSV site ? (pre-F) and site II (post-F), respectively. All the best binders were then screened through the QSAR model for his or her biological activities, including mutagenicity, level of sensitivity, biodegradability, toxicity, and carcinogenicity. Results evaluated by QSAR models denoted that 90% of the lead binders were non-mutagen and non-toxicant. Our analysis outperforms previously reported methods [58] by using structurally defined.