School Of Basic And Applied Sciences

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Author: search.filters.author.Singh, Atul KumarSubject: search.filters.subject.drug resistance

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    Acarbose Potentially Binds to the Type I Peptide Deformylase Catalytic Site and Inhibits Bacterial Growth: An In Silico and In Vitro Study
    (Bentham Science Publishers, 2022-09-23T00:00:00) Singh, Atul Kumar; Prajapati, Kumari Sunita; Kumar, Shashank
    Background: In bacteria, peptide deformylase (PDF), a metalloenzyme, removes N-formyl methio-nine from a nascent protein, which is a critical step in the protein maturation process. The enzyme is ubiqui-tously present in bacteria and possesses therapeutic target potential. Acarbose, an FDA-approved antidiabetic drug, is an alpha-glucosidase inhibitor of microbial origin. Clinical studies indicate that acarbose administration in humans can alter gut microbiota. As per the best of our knowledge, the antibacterial potential of acarbose has not been reported. Objective: The present study aimed to check the binding ability of acarbose to the catalytic site of E. coli PDF and assess its in vitro antibacterial activity. Methods: Molecular docking, molecular dynamic (MD) simulation, and MM-PBSA experiments were per-formed to study the binding potential of the catalytic site, and a disc diffusion assay was also employed to assess the antibacterial potential of acarbose. Results: Acarbose was found to form a hydrogen bond and interact with the metal ion present at the catalytic site. The test compound showed a better docking score in comparison to the standard inhibitor of PDF. MD simulation results showed energetically stable acarbose-PDF complex formation in terms of RMSD, RMSF, Rg, SASA, and hydrogen bond formation throughout the simulation period compared to the actinonin-PDF complex. Furthermore, MM-PBSA calculations showed better binding free energy (?G) of acarbose PDF than the actinonin-PDF complex. Moreover, acarbose showed in vitro antibacterial activity. Conclusion: Acarbose forms conformational and thermodynamically stable interaction with the E. coli peptide deformylase catalytic site. Results of the present work necessitate in-depth antimicrobial potential studies on the effect of acarbose on drug resistance and nonresistant bacteria. � 2022 Bentham Science Publishers.
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    Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
    (MDPI, 2022-03-30T00:00:00) Rana, Nilottam; Singh, Atul Kumar; Shuaib, Mohd; Gupta, Sanjay; Habiballah, Mahmoud M.; Alkhanani, Mustfa F.; Haque, Shafiul; Reshi, Mohd Salim; Kumar, Shashank
    Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (?G) in the M46I�saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease. � 2022 by the authors. Licensee MDPI, Basel, Switzerland.