Discovery of sulfone-resistant dihydropteroate synthase (DHPS) as a target enzyme for kaempferol, a natural flavanoid

Potshangbam, Angamba Meetei; Rathore, R. S.; Nongdam, Potshangbam

doi:10.1016/j.heliyon.2020.e03378

Cited by 8 publications

(3 citation statements)

References 54 publications

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“…Penicillin-binding proteins (PBPs) are membrane-associated proteins that play a vital role in forming cell wall 34 , 35 . As previously indicated, antibiotics target the dihydropteroate synthase enzyme 36 . This enzyme participates in the folate synthesis pathway, directly connected to nucleic acid synthesis 37 .…”

Section: Methodsmentioning

confidence: 83%

Metabolite fingerprinting of phytoconstituents from Fritillaria cirrhosa D. Don and molecular docking analysis of bioactive peonidin with microbial drug target proteins

Bhat

Mir

Sheikh

et al. 2022

Sci Rep

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Fritillaria cirrhosa D. Don (Liliaceae), a valuable and critically endangered medicinal herb of northwest India, including Jammu and Kashmir, grows in temperate to alpine regions of the Himalaya. It is known as the traditional herb for cardiovascular diseases, respiratory diseases, and metabolic disorders. The plant bulbs are precious and are used to cure many other health complications. The current study analysed the phytoconstituents by liquid chromatography-mass spectrometry (LC–MS) of different crude extracts (methanolic, petroleum ether, and ethyl acetate) of F. cirrhosa. The LC–MS analysis from the bulbs of F. cirrhosa yielded 88 bioactive compounds, with the vast majority having therapeutic applications. Further, determination of minimum inhibitory concentrations (MICs) by broth microdilution method of F. cirrhosa against tested bacterial and fungal pathogens showed remarkable results with MICs ranging between 6.25–200 µg/mL and 50–400 µg/mL, respectively. Subsequently, these 88 identified phytocompounds were tested for their bioactivity through ADMET prediction by SwissADME and in silico molecular docking studies. Results revealed that Peonidin might have maximum antibacterial and antifungal activity against various microbial protein drug targets among the phytochemical compounds identified. Furthermore, the highest binding affinity complex was subjected to molecular dynamic simulation (MDS) analysis using Desmond Schrodinger v3.8. The root-mean-square deviation (RMSD) graphs obtained through the molecular dynamic simulations indicated the true bonding interactions, further validated using the root-mean-square fluctuation (RMSF) graphs which provided a better understanding of the amino acids present in the proteins responsible for the molecular motions and fluctuations. To our best knowledge, this is the first description of the phytochemical constituents of the bulbs of F.cirrhosa analyzed through LC–MS, which show pharmacological significance. The in silico molecular docking and molecular dynamics study of peonidin was also performed to confirm its broad-spectrum activities based on the binding interactions with the antibacterial and antifungal target proteins. The present study results will create a way for the invention of herbal medicines for several ailments by using F. cirrhosa plants, which may lead to the development of novel drugs.

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Section: Methodsmentioning

confidence: 83%

Metabolite fingerprinting of phytoconstituents from Fritillaria cirrhosa D. Don and molecular docking analysis of bioactive peonidin with microbial drug target proteins

Bhat

Mir

Sheikh

et al. 2022

Sci Rep

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“…The further transformation will generate tetrahydrofolate for DNA and RNA synthesis. DHPS has two cleft for its substrates, pABA and DHPP [1], [3]- [5]. Thus, some inhibitors could mimic the structure of the substrates and act as competitive inhibitor.…”

Section: Introductionmentioning

confidence: 99%

In Silico Analysis of Chalcone Derivatives as Potential Antibacterial Agents against DHPS Enzyme

Amalina,

Tri Puspaningsing,

Suwito

2023

JATM

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Chalcone and its derivatives have been reported to perform as antibacterial agents. With the increasing threat of antibacterial resistance in pharmaceutical sector today, the discovery of new antibacterial agents is essential to accomplish good health and well-being in supporting Sustainable Development Goals (SDGs) point 4. In silico analysis is a method used to evaluate some candidates of active compounds before the synthesis process is conducted. This study aims to investigate three chalcone derivatives as potential antibacterial agents using in silico method of molecular docking. The three chalcone derivatives, 3-(4-methoxyphenyl)1-phenylprop-2-en-1-one (1), 1-(4-aminophenyl)-3-(4- methoxyphenyl) prop-2-en-1-one (2) and 1-(4-bromophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (3), were designed as pABA competitive inhibitor on DHPS and analyzed against Eschericia coli. This inhibitory mechanism was folate synthesis inhibition as precursor to DNA and RNA synthesis. Molecular docking of three chalcone derivatives with DHPS was generated using Autodock4. The results of this study showed that free energy binding (kcal/mol) of compounds (1), (2) and (3) were -6.27, -5.35 and -5.77, respectively. Besides, the Ki constant for three compounds in order were 25.50 µM, 120.32 µM and 58.84 µM, respectively. In fact, the molecular docking positions illustrated that three chalcone derivatives occupied the active site cleft. Specifically, compound (1) indicated the best outcome among the two other candidates. Meanwhile, sulfadiazine molecular docking as positive control showed lower free binding energy (-0.86 kcal/mol) and Ki constant (233.19 mM) compared to three other candidates. Therefore, three chalcone derivatives analyzed in this study demonstrated a role as potential antibacterial agents.

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“…Furthermore, sulfonamide-containing compounds demonstrated a wide range of biological activities [ 21 , 22 ], including antiviral [ 22 , 23 , 24 , 25 ], anticancer [ 26 ], and anti-inflammatory activity [ 27 ]. Sulfonamide drugs were discovered to have broad antibacterial activity [ 19 ] against bacterial infections by inhibiting the dihydropteroate synthase (DHPS) enzyme [ 20 ] through competition with 4-aminobenzoic acid (PABA) [ 28 ]. Unfortunately, sulfonamide resistance has spread and is becoming more common in community-acquired and nosocomial strains of bacteria, including S. aureus , S. mutans , and P. aeruginosa .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Physicochemical Properties and Molecular Docking of New Benzothiazole Derivatives as Antimicrobial Agents Targeting DHPS Enzyme

2022

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The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole N-arylsulphonylhydrazone with N-aryl-2-cyano-3-(dimethylamino)acrylamide, N-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of N-arylsulfonylpyridones 6a–d (yield 60–70%) and 12a–c (yield 50–60%), N-(2-(benzo[d]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide 14a–c (yield 60–65%), 4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a–c (yield 65–75%), and N′-(2-(benzo[d]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide 19a–e (yield 85–70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against S. aureus with an MIC range of 0.025 to 2.609 mM. The most active compound, 16c, exhibited superior activity against the S. aureus strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical–pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical–pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, 16a–c, had IC50 values comparable to the standard drug and revealed that compound 16b was the most active compound with an IC50 value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC50 value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds 16a–c are linked by two arene-H interactions with Lys220 within the PABA pocket.

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Discovery of sulfone-resistant dihydropteroate synthase (DHPS) as a target enzyme for kaempferol, a natural flavanoid

Cited by 8 publications

References 54 publications

Metabolite fingerprinting of phytoconstituents from Fritillaria cirrhosa D. Don and molecular docking analysis of bioactive peonidin with microbial drug target proteins

Metabolite fingerprinting of phytoconstituents from Fritillaria cirrhosa D. Don and molecular docking analysis of bioactive peonidin with microbial drug target proteins

In Silico Analysis of Chalcone Derivatives as Potential Antibacterial Agents against DHPS Enzyme

Synthesis, Physicochemical Properties and Molecular Docking of New Benzothiazole Derivatives as Antimicrobial Agents Targeting DHPS Enzyme

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