Identification of secondary metabolites from Crescentia cujete as promising antibacterial therapeutics targeting type 2A topoisomerases through molecular dynamics simulation

Aribisala, ‪Jamiu Olaseni; Abdulsalam, Rukayat Abiola; Dweba, Yamkela; Khumbulani, Madonsela; Sabiu, Saheed

doi:10.1016/j.compbiomed.2022.105432

Cited by 17 publications

(10 citation statements)

References 32 publications

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“…Thus, suggesting the likelihood of the compounds having good interaction with PTP1B, this is consistent with previous studies on molecular docking of compounds [40]. However, there are reports or studies where flavonoids such as quercetin, morin, isorhamnetin, vitexin, isoorientin, and luteolin tend to be better posed with enzymes such as chymotrypsin-like protease, alpha-glucosidase, and PTP1B than standard inhibitors [20,[41][42][43][44]. However, due to limitations of molecular docking serving only as a preliminary analysis of a ligand's affinity for protein's binding pocket, MD simulation was performed over a -100 ns to account for the protein's behavior upon binding of the respective flavonoid glycosides, through better elucidation of the ligand's affinity by binding free energy, as well as vital conformational information regarding structural stability, flexibility, and compactness taken as post-MD simulation indices [45].…”

Section: Resultssupporting

confidence: 90%

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Rampadarath

Balogun

Pillay

et al. 2022

Journal of Diabetes Research

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Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signaling pathway, has gained attention as a validated druggable target in the management of type 2 diabetes mellitus (T2DM). The lack of clinically approved PTP1B inhibitors has continued to prompt research in plant-derived therapeutics possibly due to their relatively lesser toxicity profiles. Flavonoid C-glycosides are one of the plant-derived metabolites gaining increased relevance as antidiabetic agents, but their possible mechanism of action remains largely unknown. This study investigates the antidiabetic potential of flavonoid C-glycosides against PTP1B in silico and in vitro. Of the seven flavonoid C-glycosides docked against the enzyme, three compounds (apigenin, vitexin, and orientin) had the best affinity for the enzyme with a binding score of –7.3 kcal/mol each, relative to –7.4 kcal/mol for the reference standard, ursolic acid. A further probe (in terms of stability, flexibility, and compactness) of the complexes over a molecular dynamics time study of 100 ns for the three compounds suggested orientin as the most outstanding inhibitor of PTP1B owing to its overall -34.47 kcal/mol binding energy score compared to ursolic acid (-19.24 kcal/mol). This observation was in accordance with the in vitro evaluation result, where orientin had a half maximal inhibitory concentration (IC50) of 0.18 mg/ml relative to 0.13 mg/ml for the reference standard. The kinetics of inhibition of PTP1B by orientin was mixed-type with V max and K m values of 0.004 μM/s and 0.515 μM. Put together, the results suggest orientin as a potential PTP1B inhibitor and could therefore be further explored in the management T2DM as a promising therapeutic agent.

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Section: Resultssupporting

confidence: 90%

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Rampadarath

Balogun

Pillay

et al. 2022

Journal of Diabetes Research

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“…The bound systems with average values ranging between 3.31 and 4.90 Å, generally had a reduced RMSD value compared to the apo-PBP2x (6.32 Å) with lysidicichin and ECMG having the lowest values, which compared well with amoxicillin (Table 3). The reduced RMSD value of PBP2x following binding of ligands generally denotes enhanced thermodynamic stability of the complexes [29]. This observation agrees with the report of Sainsbury et al .…”

Section: Resultssupporting

confidence: 89%

Cheminformatics identification of phenolics as modulators of penicillin binding protein (PBP) 2x ofStreptococcus pneumoniaetowards interventive antibacterial therapy

Aribisala,

S’thebe,

Sabiu

2023

Preprint

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Infections caused by multidrug-resistantStreptococcus pneumoniaeremain the leading cause of pneumonia-related deaths in children < 5 years globally, and mutations in penicillin-binding protein (PBP) 2x have been identified as the major cause of resistance in the organism to beta-lactams. Thus, the development of new modulators with enhanced binding of PBP2x is highly encouraged. In this study, phenolics, due to their reported antibacterial activities, were screened against the active site of PBP2x using structure-based pharmacophore and molecular docking techniques, and the ability of the top-hit phenolics to inhibit the active and allosteric sites of PBP2x was refined through 120 ns molecular dynamic simulation. Except for gallocatechin gallate and lysidicichin, respectively, at the active and allosteric sites of PBP2x, the top-hit phenolics had higher negative binding free energy (ΔGbind) than amoxicillin [active site (−19.23 kcal/mol), allosteric site (−33.75 Kcal/mol)]. Although silicristin had the best broad-spectrum effects at the active (−38.41 kcal/mol) and allosteric (−50.54 kcal/mol) sites of PBP2x, the high thermodynamic entropy (4.90 Å) of the resulting complex might suggest the need for its possible structural refinement for enhanced potency. Interestingly, silicristin had a predicted synthetic feasibility score of < 5 and quantum calculations using the DFT B3LYP/6-31G+ (dp) revealed that silicristin is less stable and more reactive than amoxicillin. These findings point to the possible benefits of the top-hit phenolics, and most especially silicristin, in the direct and synergistic treatment of infections caused byS. pneumoniae. Accordingly, silicristin is currently the subject of further confirmatoryin vitroresearch.

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“…A total of 73 compounds ( Supplementary Table S1 ), 58 of which had been reported to have been isolated from different parts of C. cujete [ 13 , 15 ], 14 phytoconstituents from corn silk [ 11 ] and some of those previously identified as promising anti-SC-2 metabolites [ 14 ] were used in this study and will be regarded as LOCM going forward.…”

Section: Methodsmentioning

confidence: 99%

“…In short, Galaxy Europe’s “molecule-to-fingerprint” program was used to convert the chemical smile format into “pen Babel FP2 fingerprints”. The “Open Babel FP2 fingerprints” were then clustered using the Taylor-Butina and NxN clustering fingerprinting techniques with thresholds of 0.8 and 0.0, respectively [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

Cheminformatics Bioprospection of Broad Spectrum Plant Secondary Metabolites Targeting the Spike Proteins of Omicron Variant and Wild-Type SARS-CoV-2

Aribisala

Aruwa²,

Uthman³

et al. 2022

Metabolites

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The spike protein (SP) of SARS-CoV-2 (SC-2) is susceptible to high mutation and has contributed to the multiple waves of COVID-19 being experienced. Hence, targeting the SP remains a logical approach in the development of potent therapeutics against SARS-CoV-2. Here, a computational technique was adopted to identify broad-spectrum plant secondary metabolites with indigenous relevance in the management of respiratory infections against the SPs of the SC-2 wild- type (SC-2WT) and omicron variants. Following 100 ns molecular dynamic (MD) simulation and binding free energy calculation of the top five compounds identified through molecular docking, maysin (SC-2WT (−34.85 kcal/mol), omicron (−38.88 kcal/mol)) and geraniin (SC-2WT (−36.90 kcal/mol) omicron (−31.28 kcal/mol)) had better broad-spectrum activities for the investigated SPs than zafirlukast (SC-2WT (−33.73 kcal/mol) omicron (−22.38 kcal/mol)). Furthermore, 6-hydroxycyanidin-3-rutinoside (−42.97 kcal/mol) and kaempferol-7-glucoside (−37.11 kcal/mol) had the best affinity for the SPs of omicron and SC-2WT, respectively. Interestingly, except for Kaempferol-7-glucoside against omicron SP, all the top-ranked compounds were thermodynamically stable with the SP of both variants, and this observation was linked to the number, nature, and bond length in the resulting complexes in each case. Also, except for geraniin, all the top-ranked compounds had lower toxicity profiles compared to zafirlukast and this could be attributed to their phenolic moieties. Nevertheless, the in vitro and in vivo confirmation of the activities observed in this study is recommended, especially for maysin and geraniin with the best broad-spectrum activity, towards development of COVID-19 drug candidates.

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Identification of secondary metabolites from Crescentia cujete as promising antibacterial therapeutics targeting type 2A topoisomerases through molecular dynamics simulation

Cited by 17 publications

References 32 publications

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Cheminformatics identification of phenolics as modulators of penicillin binding protein (PBP) 2x ofStreptococcus pneumoniaetowards interventive antibacterial therapy

Cheminformatics Bioprospection of Broad Spectrum Plant Secondary Metabolites Targeting the Spike Proteins of Omicron Variant and Wild-Type SARS-CoV-2

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