Computational Docking-Based Evaluation of Novel β-Lactam Analogues Against Treponema pallidum via RhoGTPase-Activating Protein (1RT2) Inhibition for Enhanced Antisyphilitic Activity
DOI:
https://doi.org/10.63682/jns.v14i32S.7934Keywords:
β-lactam analogues, Treponema pallidum, molecular docking, RhoGTPase, antispirochetal agentsAbstract
Syphilis, caused by the spirochete Treponema pallidum, remains a globally resurgent sexually transmitted infection with significant public health implications. Despite the proven efficacy of Penicillin G, emerging therapeutic challenges such as patient hypersensitivity, pharmacokinetic limitations in neurosyphilis, and resistance trends in related bacterial species necessitate the identification of novel or optimized β-lactam analogues. This study employed a structure-based drug design approach to evaluate the binding affinity and molecular interactions of five β-lactam derivatives Penicillin G, Penicillin V, Ampicillin, Amoxicillin, and Methicillin against RhoGTPase-activating protein (PDB ID: 1RT2), a surrogate target relevant to the regulation of host-pathogen cytoskeletal signaling. Molecular docking simulations were performed using AutoDock Vina and PyRx, and interaction analyses were visualized using Chimera and LigPlot+. Penicillin G exhibited the most favorable docking score (–9.1 kcal/mol), forming strong hydrogen bonds and π–π stacking with active site residues such as TYR181, TRP229, and GLN64, indicating a highly stable ligand–receptor complex. Comparative analysis revealed that increased steric bulk and polar substitutions in other analogues hindered optimal binding. Structure–activity relationship (SAR) findings suggest that minimal side chain substitutions and hydrophobic compatibility significantly enhance 1RT2 binding. These results highlight Penicillin G as a potent RhoGTPase pathway modulator and reinforce its superiority among β-lactam analogues for antisyphilitic therapy. Furthermore, this docking-based study provides mechanistic insights for the rational design of next-generation spirocheticidal agents targeting regulatory protein systems.
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Vishvakrama P, Sharma S. Liposomes: an overview. Journal of Drug Delivery and Therapeutics. 2014 Jun 24:47-55.
R. Zarrilli, D. Vitale, A. Di Popolo, M. Bagattini, Z. Daoud, A. U. Khan, C. Afif, and M. Triassi, “A plasmid-borne blaOXA-58 gene confers imipenem resistance to Acinetobacter baumannii isolates from a Lebanese hospital,” Antimicrob. Agents Chemother., vol. 52, pp. 4115–4120, 2008.
Vishvakarma P. Design and development of montelukast sodium fast dissolving films for better therapeutic efficacy. Journal of the Chilean Chemical Society. 2018 Jun;63(2):3988-93.
R. Cantón and T. M. Coque, “The CTX-M beta-lactamase pandemic,” Curr. Opin. Microbiol., vol. 9, pp. 466–475, 2006.
Prabhakar Vishvakarma, Jaspreet Kaur, Gunosindhu Chakraborthy, Dhruv Kishor Vishwakarma, Boi Basanta Kumar Reddy, Pampayya Thanthati, Shaik Aleesha and Yasmin Khatoon, “Nephroprotective potential of Terminalia arjuna against cadmium-induced renal toxicity by in-vitro study”, J. Exp. Zool. India 2025, Volume: 28, Issue No: 1(January), Page No: 939, DOI: 10.51470/jez.2025.28.1.939
P. Pattanaik et al., “Strategic design of an effective β-lactamase inhibitor LN-1-255, a 6-alkylidene-2′-substituted penicillin sulfone,” J. Biol. Chem., vol. 284, pp. 945–953, 2009.
Devidas Gulabrao Bachhav, Dharmesh Sisodiya, Gita Chaurasia, Virendra Kumar, Mohammed Sofiqul Mollik, Prabhu K. Halakatti, Dharmesh Trivedi, Prabhakar Vishvakarma*, “Development And In-Vitro Evaluation of Niosomal Fluconazole for Fungal Treatment”, J. Exp. Zool. India Vol. 27, No. 2, pp. 1539-1547, 2024.
K. Arnold, L. Bordoli, J. Kopp, and T. Schwede, “The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling,” Bioinformatics, vol. 22, pp. 195–201, 2006.
N. Guex and C. M. Peitsch, “SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling,” Electrophoresis, vol. 18, pp. 2714–2723, 1997.
R. A. Laskowski, V. V. Chistyakov, and J. M. Thornton, “PDBsum more: New summaries and analyses of the known 3D structures of proteins and nucleic acids,” Nucleic Acids Res., vol. 33, pp. D266–D268, 2005.
Vishvakarma P, Mandal S, Pandey J, Bhatt AK, Banerjee VB, Gupta JK. An Analysis of The Most Recent Trends In Flavoring Herbal Medicines In Today's Market. Journal of Pharmaceutical Negative Results. 2022 Dec 31:9189-98.
G. Jones, P. Willett, and R. C. Glen, “Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation,” J. Mol. Biol., vol. 245, pp. 43–53, 1995.
E. F. Pettersen et al., “UCSF Chimera—A visualization system for exploratory research and analysis,” J. Comput. Chem., vol. 25, pp. 1605–1612, 2004.
J. D. Thompson, D. G. Higgins, and T. J. Gibson, “CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice,” Nucleic Acids Res., vol. 22, pp. 4673–4680, 1994.
Prabhakar V, Agarwal S, Chauhan R, Sharma S. Fast dissolving tablets: an overview. International Journal of Pharmaceutical Sciences: Review and Research. 2012;16(1):17.
A. Fleming, “On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzæ,” Br. J. Exp. Pathol., vol. 10, pp. 226–233, 1929. doi: 10.1093/clinids/2.1.129.
S. M. Drawz and R. A. Bonomo, “Three decades of β-lactamase inhibitors,” Clin. Microbiol. Rev., vol. 23, pp. 160–201, 2010. doi: 10.1128/CMR.00037-09.
B. Thakuria and K. Lahon, “The beta lactam antibiotics as an empirical therapy in a developing country: An update on their current status and recommendations to counter the resistance against them,” J. Clin. Diagn. Res., vol. 7, pp. 1207–1214, 2013. doi: 10.7860/JCDR/2013/5239.3052.
R. Rodriguez-Herrera et al., “Enzymes in the pharmaceutical industry for β-lactam antibiotic production,” in Enzymes in Food Biotechnology: Production, Applications, and Future Prospects, M. Kuddus, Ed., London, UK: Elsevier, 2019, pp. 627–643.
X. Zeng and J. Lin, “Beta-lactamase induction and cell wall metabolism in gram-negative bacteria,” Front. Microbiol., vol. 4, pp. 1–9, 2013. doi: 10.3389/fmicb.2013.00128.
C. L. Tooke et al., “β-Lactamases and β-lactamase inhibitors in the 21st century,” J. Mol. Biol., vol. 431, pp. 3472–3500, 2019. doi: 10.1016/j.jmb.2019.04.002.
C. C. S. Fuda, J. F. Fisher, and S. Mobashery, “Beta-lactam resistance in Staphylococcus aureus: The adaptive resistance of a plastic genome,” Cell. Mol. Life Sci., vol. 62, pp. 2617–2633, 2005. doi: 10.1007/s00018-005-5148-6.
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