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Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists

OBJECTIVE: Typhoid fever, a disease caused by Salmonella typhi, is a leading cause of morbidity and mortality, particularly in developing nations. The evolution of resistance mechanisms to existing antibiotics has necessitated a search for newer drug candidates. This study used computer aided drug d...

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Autores principales: Ameji, John P., Uzairu, Adamu, Shallangwa, Gideon A., Uba, Sani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taibah University 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9957885/
https://www.ncbi.nlm.nih.gov/pubmed/36852248
http://dx.doi.org/10.1016/j.jtumed.2022.12.010
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author Ameji, John P.
Uzairu, Adamu
Shallangwa, Gideon A.
Uba, Sani
author_facet Ameji, John P.
Uzairu, Adamu
Shallangwa, Gideon A.
Uba, Sani
author_sort Ameji, John P.
collection PubMed
description OBJECTIVE: Typhoid fever, a disease caused by Salmonella typhi, is a leading cause of morbidity and mortality, particularly in developing nations. The evolution of resistance mechanisms to existing antibiotics has necessitated a search for newer drug candidates. This study used computer aided drug design techniques to design novel antibiotics that function by antagonizing SipB, an effector protein of the bacterium that is responsible for its pathogenicity and virulence in eukaryotic host cells. METHODS: A data set of 32 bioactive molecules with established antibacterial activity against S. typhi was retrieved from the PubChem data base; optimized through a DFT approach in Spartan 14 software; and further subjected to QSAR modeling in BIOVIA-Accelrys Material Studio. The validated model (R(2) = 0.80, R(2)(Adj) = 0.78, Q(2)(LOO) = 0.74, R(2)(pred) = 0.54, lack of fit = 0.07) revealed the dominant influence of MATS6c and E3p descriptors on the observed antibacterial activity of the compounds. Information from the model was used to optimize the structures of selected lead compounds in the data set, thus leading to the design of a highly potent set of novel analogues denoted D-1, D-2 and D-3. RESULTS: The predicted MIC values of D-1, D-2 and D-3 were 1.03, 0.73 and 0.30 μg/mL, respectively. Furthermore, molecular docking studies on these novel ligands against the active sites of SipB revealed binding energy values of −8.0, −7.7 and −7.7 kcal/mol for D-1, D-2 and D-3, respectively. These values were better than the −7.0 kcal/mol recorded for ciprofloxacin, the reference antibiotic used herein for quality assurance. In addition, drug-likeness and ADMET evaluation of the designed compounds revealed that they are orally bioavailable and exhibit excellent pharmacokinetic and toxicological profiles. CONCLUSION: The current findings may provide a roadmap for the discovery of more potent antibiotics against S. typhi.
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spelling pubmed-99578852023-02-26 Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists Ameji, John P. Uzairu, Adamu Shallangwa, Gideon A. Uba, Sani J Taibah Univ Med Sci Original Article OBJECTIVE: Typhoid fever, a disease caused by Salmonella typhi, is a leading cause of morbidity and mortality, particularly in developing nations. The evolution of resistance mechanisms to existing antibiotics has necessitated a search for newer drug candidates. This study used computer aided drug design techniques to design novel antibiotics that function by antagonizing SipB, an effector protein of the bacterium that is responsible for its pathogenicity and virulence in eukaryotic host cells. METHODS: A data set of 32 bioactive molecules with established antibacterial activity against S. typhi was retrieved from the PubChem data base; optimized through a DFT approach in Spartan 14 software; and further subjected to QSAR modeling in BIOVIA-Accelrys Material Studio. The validated model (R(2) = 0.80, R(2)(Adj) = 0.78, Q(2)(LOO) = 0.74, R(2)(pred) = 0.54, lack of fit = 0.07) revealed the dominant influence of MATS6c and E3p descriptors on the observed antibacterial activity of the compounds. Information from the model was used to optimize the structures of selected lead compounds in the data set, thus leading to the design of a highly potent set of novel analogues denoted D-1, D-2 and D-3. RESULTS: The predicted MIC values of D-1, D-2 and D-3 were 1.03, 0.73 and 0.30 μg/mL, respectively. Furthermore, molecular docking studies on these novel ligands against the active sites of SipB revealed binding energy values of −8.0, −7.7 and −7.7 kcal/mol for D-1, D-2 and D-3, respectively. These values were better than the −7.0 kcal/mol recorded for ciprofloxacin, the reference antibiotic used herein for quality assurance. In addition, drug-likeness and ADMET evaluation of the designed compounds revealed that they are orally bioavailable and exhibit excellent pharmacokinetic and toxicological profiles. CONCLUSION: The current findings may provide a roadmap for the discovery of more potent antibiotics against S. typhi. Taibah University 2022-12-31 /pmc/articles/PMC9957885/ /pubmed/36852248 http://dx.doi.org/10.1016/j.jtumed.2022.12.010 Text en © 2022 [The Author/The Authors] https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Ameji, John P.
Uzairu, Adamu
Shallangwa, Gideon A.
Uba, Sani
Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title_full Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title_fullStr Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title_full_unstemmed Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title_short Obstructing Salmonella typhi's virulence in eukaryotic cells through design of its SipB protein antagonists
title_sort obstructing salmonella typhi's virulence in eukaryotic cells through design of its sipb protein antagonists
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9957885/
https://www.ncbi.nlm.nih.gov/pubmed/36852248
http://dx.doi.org/10.1016/j.jtumed.2022.12.010
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