Chowdhury, D. U. S. | Search bioRxiv

bioRxiv2024

Identification of potential inhibitors against Inosine 5'-Monophosphate Dehydrogenase of Cryptosporidium parvum through an integrated in silico approach

The protozoan parasite Cryptosporidium, found in several vertebrates, including humans, is the source of the global infection known as cryptosporidiosis, which manifests as acute gastroenteritis, abdominal pain, and diarrhea. Although infections in certain individuals have been linked to other species, Cryptosporidium parvum is the main cause of illnesses in humans. Lactate Dehydrogenase, Inosine 5'-Monophosphate Dehydrogenase (IMPDH), and several other targets have been identified by the genome sequencing of C. parvum. Bioactive phytochemicals derived from nature have enormous potential as anti-cryptosporidiosis agents. The study aimed to identify new anti-cryptosporidial agents that work against the IMPDH of the parasite by using integrated in silico approaches. In this study, a total of 24 bioactive phytochemicals were screened virtually through molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. Four lead compounds were identified, including Brevelin A (-8.9 kcal/mol), Vernodalin (-8.7 kcal/mol), Luteolin (-8.6 kcal/mol), and Pectolinarigenin (-8.1 kcal/mol), against the IMPDH protein (PDB ID: 4IXH) from the parasite. All the lead compounds had excellent pharmacokinetic and pharmacodynamic characteristics. The toxicity analysis showed satisfactory results with no major side effects. All of the selected compounds showed no violation of Lipinskis rules of five, indicating the possibility of oral bioavailability as potential drug candidates. In the majority of cases, target class prediction-identified enzymes, as well as investigational and experimental drugs, have been found to have structural similarities to the lead compounds. With significant biochemical interactions, all of the targeted phytochemical compounds have demonstrated excellent pharmacokinetics and better bioavailabilities. The findings strongly recommend in vitro experimental studies to aid in the development of novel therapeutics against Cryptosporidium parvum.

bioinformatics↗

bioRxiv2022

Exploring different virulent proteins of human respiratory syncytial virus for designing a novel epitope-based polyvalent vaccine: Immunoinformatics and molecular dynamics approaches

Human Respiratory Syncytial Virus (RSV) is one of the most prominent causes of lower respiratory tract infections (LRTI), contributory to infecting people from all age groups - a majority of which comprises infants and children. The implicated severe RSV infections lead to numerous deaths of multitudes of the overall population, predominantly the children, every year. Consequently, despite several distinctive efforts to develop a vaccine against the RSV as a potential countermeasure, there is no approved or licensed vaccine available yet, to control the RSV infection effectively. Therefore, through the utilization of immunoinformatics tools, a computational approach was taken in this study, to design and construct a multi-epitope polyvalent vaccine against the RSV-A and RSV-B strains of the virus. Potential predictions of the T-cell and B-cell epitopes were followed by extensive tests of antigenicity, allergenicity, toxicity, conservancy, homology to human proteome, transmembrane topology, and cytokine-inducing ability. The most promising epitopes (i.e. 13 CTL epitopes, 9 HTL epitopes, and 10 LBL epitopes) exhibiting full conservancy were then selected for designing the peptide fusion with appropriate linkers, having hBD-3 as the adjuvant. The peptide vaccine was modeled, refined, and validated to further improve the structural attributes. Following this, molecular docking analysis with specific TLRs was carried out which revealed excellent interactions and global binding energies. Additionally, molecular dynamics (MD) simulation was conducted which ensured the stability of the interactions between vaccine and TLR. Furthermore, mechanistic approaches to imitate and predict the potential immune response generated by the administration of vaccines were determined through immune simulations. Owing to an overall evaluation, in silico cloning was carried out in efforts to generate recombinant pETite plasmid vectors for subsequent mass production of the vaccine peptide, incorporated within E.coli. However, more in vitro and in vivo experiments can further validate its efficacy against RSV infections.

immunology↗