Drug repurposing: Fusidic acid as a potential inhibitor of M. tuberculosis FtsZ polymerization – Insight from DFT calculations, molecular docking and molecular dynamics simulations

Akinpelu, Olayinka I.; Lawal, Monsurat M.; Kumalo, Hezekiel M.; Mhlongo, Ndumiso N.

doi:10.1016/j.tube.2020.101920

Cited by 27 publications

(17 citation statements)

References 44 publications

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“…The RMSF calculations were estimated from the 100 ns trajectories of the systems and the results are shown in Figure 4. Similar to our previous studies on Mtb-FtsZ inhibition, 13,35 major differences in residue fluctuation in the systems were observed in residues 50-75, 120-140 and 230-270 which are the regions where the majority of the binding site residues are located. While the compounds' influences are observable almost on all the residues in the receptor, their effects are more noticeable on the residues closer to the binding pocket of the protein.…”

Section: Root Mean Square Fluctuation and Dssp Analysissupporting

confidence: 88%

“…6,7 Different classes of compounds like taxanes, citrate, trisubstituted benzimidazoles, totarol, sulindac, zantrins, berberine, and many more have been identified as possible antitubercular agents targeting Mtb-FtsZ polymerisation and/or GTPase activities. [8][9][10][11][12][13] Berberine is one of the active compounds of crude extract of roots and rhizomes of Hydrastis canadensis (also popularly called golden seal) which is one of the most widely used medicinal plants in the world. The extract from golden seal is used to treat many infections, including tuberculosis.…”

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confidence: 99%

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Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Akinpelu

Kumalo

Mhlongo

et al. 2021

J of Molecular Recognition

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Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperaturesensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

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Section: Root Mean Square Fluctuation and Dssp Analysissupporting

confidence: 88%

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confidence: 99%

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Akinpelu

Kumalo

Mhlongo

et al. 2021

J of Molecular Recognition

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“…They hope to synthesize and screen FA derivatives to study the antituberculosis activity and mechanism of action (Kigondu et al, 2014). In a recent study, Akinpelu et al found that FA was a potential inhibitor of M. tuberculosis filamentous temperature sensitive mutant Z (FtsZ) by computer methods, including density function theory (DFT), molecular docking, and molecular dynamics simulations (Akinpelu et al, 2020).…”

Section: Anti-m Tuberculosis Activitymentioning

confidence: 99%

Bioactivities and Structure–Activity Relationships of Fusidic Acid Derivatives: A Review

Long

Zhang

et al. 2021

Front. Pharmacol.

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Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.

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“…Fusidic acid (FA) is a widely used steroidal bacteriostatic antibiotic drug with a tetracyclic ring. It has been successfully used for the treatment of infections caused by Gram-positive species and especially Staphylococcus aureus [17,18]. Its bioavailability is rate-limited with its dissolution and it is a Biopharmaceutics Classification System (BCS) Class-II drug [4].…”

Section: Introductionmentioning

confidence: 99%

Preparation and detailed characterization of fusidic acid loaded in situ gel formulations for ophthalmic application

Rençber¹,

Bulbul²,

Okur³

et al. 2021

jrp

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Drug repurposing: Fusidic acid as a potential inhibitor of M. tuberculosis FtsZ polymerization – Insight from DFT calculations, molecular docking and molecular dynamics simulations

Cited by 27 publications

References 44 publications

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Bioactivities and Structure–Activity Relationships of Fusidic Acid Derivatives: A Review

Preparation and detailed characterization of fusidic acid loaded in situ gel formulations for ophthalmic application

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