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In Silico Drug Designing for ala438 Deleted Ribosomal Protein S1 (RpsA) on the Basis of the Active Compound Zrl15.

ABSTRACT: Pyrazinoic acid-resistant tuberculosis is a severe chronic disorder. First-line drugs specifically target the ribosomal protein subunit-1 (RpsA) and stop trans-translation in the wild-type bacterium, causing bacterial cell death. In mutant bacterial strain, the deletion of ala438 does not let the pyrazinoic acid to bind to the active site of RpsA and ensures that the bacterium survives. Hence, such tuberculosis cases require an immediate and successful regime. The current study was designed to identify inhibitors that could bind to the mutant state of the RpsA protein. Initially, a pharmacophore model was generated based on the recently published most potent inhibitor for the mutant state of RpsA, i.e., zrl15. The validated pharmacophore model was further used for virtual screening of two chemical libraries, i.e., ZINC and ChemBridge. After applying the Lipinski rule of five (Ro5), a total of 260 and 749 hits from the ChemBridge and ZINC libraries, respectively, were identified using pharmacophore mapping. These hits were then docked into the active site of the mutant state of the RpsA protein, and later, the top 150 compounds from each library were chosen based on the docking score. A total of 21 compounds were shortlisted from each library based on the best protein-ligand interactions. Finally, a total of 05 compounds were subjected to molecular dynamics study to examine the dynamic behavior of each compound in the active site of the mutant state of the RpsA protein. The results revealed that all compounds had good chemical properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET), and there was no Pan Assay Interference (PAINS) or deviation from Ro5, indicating that these compounds could be useful antagonists for the mutant state of the RpsA protein.

SUBMITTER: Wadood A

PROVIDER: S-EPMC8756442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Resistance to key first-line drugs is a major hurdle to achieve the global end tuberculosis (TB) targets. A prodrug, pyrazinamide (PZA) is the only drug, effective in latent TB, recommended in drug resistance and susceptible Mycobacterium tuberculosis (MTB) isolates. The prodrug conversion into active form, pyrazinoic acid (POA), required the activity of pncA gene encoded pyrazinamidase (PZase). Although pncA mutations have been commonly associated with PZA resistance but a small number of resistance cases have been associated with mutationss in RpsA protein. Here in this study a total of 69 PZA resistance isolates have been sequenced for pncA mutations. However, samples that were found PZA resistant but pncA wild type (pncAWT), have been sequenced for rpsA and panD genes mutation. We repeated a drug susceptibility testing according to the WHO guidelines on 18 pncAWT MTB isolates. The rpsA and panD genes were sequenced. Out of total 69 PZA resistant isolates, 51 harbored 36 mutations in pncA gene (GeneBank Accession No. MH46111) while, fifteen different mutations including seven novel, were detected in the fourth S1 domain of RpsA known as C-terminal (MtRpsACTD) end. We did not detect any mutations in panD gene. Among the rpsA mutations, we investigated the molecular mechanism of resistance behind mutations, D342N, D343N, A344P, and I351F, present in the MtRpsACTD through molecular dynamic simulations (MD). WT showed a good drug binding affinity as compared to mutants (MTs), D342N, D343N, A344P, and I351F. Binding pocket volume, stability, and fluctuations have been altered whereas the total energy, protein folding, and geometric shape analysis further explored a significant variation between WT and MTs. In conclusion, mutations in MtRpsACTD might be involved to alter the RpsA activity, resulting in drug resistance. Such molecular mechanism behind resistance may provide a better insight into the resistance mechanism to achieve the global TB control targets.

Project description:BackgroundThe novel coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the ongoing 2019-2020 pandemic. SARS-CoV-2 is a positive-sense single-stranded RNA coronavirus. Effective countermeasures against SARS-CoV-2 infection require the design and development of specific and effective vaccine candidates.ObjectiveTo address the urgent need for a SARS-CoV-2 vaccine, in the present study, we designed and validated one cytotoxic T lymphocyte (CTL) and one helper T lymphocyte (HTL) multi-epitope vaccine (MEV) against SARS-CoV-2 using various in silico methods.MethodsBoth designed MEVs are composed of CTL and HTL epitopes screened from 11 Open Reading Frame (ORF), structural and nonstructural proteins of the SARS-CoV-2 proteome. Both MEVs also carry potential B-cell linear and discontinuous epitopes as well as interferon gamma-inducing epitopes. To enhance the immune response of our vaccine design, truncated (residues 10-153) Onchocerca volvulus activation-associated secreted protein-1 was used as an adjuvant at the N termini of both MEVs. The tertiary models for both the designed MEVs were generated, refined, and further analyzed for stable molecular interaction with toll-like receptor 3. Codon-biased complementary DNA (cDNA) was generated for both MEVs and analyzed in silico for high level expression in a mammalian (human) host cell line.ResultsIn the present study, we screened and shortlisted 38 CTL, 33 HTL, and 12 B cell epitopes from the 11 ORF protein sequences of the SARS-CoV-2 proteome. Moreover, the molecular interactions of the screened epitopes with their respective human leukocyte antigen allele binders and the transporter associated with antigen processing (TAP) complex were positively validated. The shortlisted screened epitopes were utilized to design two novel MEVs against SARS-CoV-2. Further molecular models of both MEVs were prepared, and their stable molecular interactions with toll-like receptor 3 were positively validated. The codon-optimized cDNAs of both MEVs were also positively analyzed for high levels of overexpression in a human cell line.ConclusionsThe present study is highly significant in terms of the molecular design of prospective CTL and HTL vaccines against SARS-CoV-2 infection with potential to elicit cellular and humoral immune responses. The epitopes of the designed MEVs are predicted to cover the large human population worldwide (96.10%). Hence, both designed MEVs could be tried in vivo as potential vaccine candidates against SARS-CoV-2.

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In Silico Drug Designing for ala438 Deleted Ribosomal Protein S1 (RpsA) on the Basis of the Active Compound Zrl15.

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