Structure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting α-Helix Backbone Oxygen by Halogen Bonding

Hsieh, Chao-Ming; Chen, Chun-Yi; Chern, Ji‐Wang; Chan, Nei-Li

doi:10.1021/acs.jmedchem.0c00853

Cited by 12 publications

(14 citation statements)

References 61 publications

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“…10B ). These kinds of movements have been observed previously in recent articles where the H-loop moves inward as a result of binding of sildenafil to the Q-pocket, 25 similar pattern was observed in case of Sa. The effect of ligand binding on protein shape (contraction/expansion) and structure was observed by calculating the radius of gyration ( R g ) of the protein over the trajectories.…”

Section: Resultssupporting

confidence: 86%

Salazinic acid attenuates male sexual dysfunction and testicular oxidative damage in streptozotocin-induced diabetic albino rats

et al. 2023

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Section: Resultssupporting

confidence: 86%

Salazinic acid attenuates male sexual dysfunction and testicular oxidative damage in streptozotocin-induced diabetic albino rats

et al. 2023

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“…The catalytic domain of PDE5A (residues 535-862; GenBank accession number BC126233.1) was subcloned into the T7 promoter-driven expression vector pET21b with a 6 × His-tag at the C-terminus ( Hsieh et al, 2020 ). The recombinant plasmid was transformed into E. coli strain BL21 (DE3) and grown in an autoinducing medium ( Studier 2005 ) containing 50 μg/mL ampicillin at 37 C until OD600 = 0.6–0.7, then induced protein expression at 15°C for 40 h. The PDE5A protein was purified through the Ni-NTA column (Thermo Scientific) and further purified by the HiPrep™26/60 Sephacryl™-S-200HR column (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

A label-free LC/MS-based enzymatic activity assay for the detection of PDE5A inhibitors

Zhang²,

Zhong³

et al. 2023

Front. Chem.

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Phosphodiesterase type 5 (PDE5), a cyclic nucleotide phosphodiesterase, controls the duration of the cyclic guanosine monophosphate (cGMP) signal by hydrolyzing cGMP to GMP. Inhibiting the activity of PDE5A has proven to be an effective strategy for treating pulmonary arterial hypertension and erectile dysfunction. Current enzymatic activity assay methods for PDE5A mainly use fluorescent or isotope-labeled substrates, which are expensive and inconvenient. Here, we developed an LC/MS-based enzymatic activity assay for PDE5A without labeling, which detects the enzymatic activity of PDE5A by quantifying the substrate cGMP and product GMP at a concentration of 100 nM. The accuracy of this method was verified by a fluorescently labeled substrate. Moreover, a new inhibitor of PDE5A was identified by this method and virtual screening. It inhibited PDE5A with an IC50 value of 870 nM. Overall, the proposed strategy provides a new method for screening PDE5A inhibitors.

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“…The reason behind this property is its unique structure which includes aryl halide (-Cl) rather than nucleotide (purine base-sugarphosphodiester bonds) forming backbone of earlier discovered first line drugs for ED. [24] In the recent study of Hsieh et al (2020) [25], the structure of PDE5-AVA complex was determined at 1.9 Å resolution. The PDE5 inhibitors are known to be act by competing with cGMP for binding to the active site.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Characteristics and Analytical Methods of Novel PDE5 Inhibitor Avanafil: An Update

Shrivastava¹

2022

Hacettepe University Journal of the Faculty of Pharmacy

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Erectile dysfunction (ED) affects middle and older age and occurrence increasing with age of men. PDE5 inhibitors are commonly used for the treatment of ED. The incidences of adulteration of PDE5 inhibitors with herbal aphrodisiacs is evident in almost every part of world. Avanafil (AVA) is novel PDE5 inhibitor with advantage of fast action. The literatures and various analytical methods presented in this review was obtained by searching various databases like pubmed, medline, eurekaselect, sciencedirect, wiley and taylor and francis journals. The services of google scholar were also utilized for searching some literature. The literature search was performed to summarize characteristics, synthesis and analytical methods for determination of AVA. Different spectrophotometric methods, chromatographic and ion mobility mass spectrometric methods are available in the method. The possibility for the development of green analytical method is also discussed. The various analytical methods and characteristics for AVA analysis are described. The methods for determination of AVA as adulterants and in pharmaceutical formulations including stability indicating methods.

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Structure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting α-Helix Backbone Oxygen by Halogen Bonding

Cited by 12 publications

References 61 publications

Salazinic acid attenuates male sexual dysfunction and testicular oxidative damage in streptozotocin-induced diabetic albino rats

Salazinic acid attenuates male sexual dysfunction and testicular oxidative damage in streptozotocin-induced diabetic albino rats

A label-free LC/MS-based enzymatic activity assay for the detection of PDE5A inhibitors

Characteristics and Analytical Methods of Novel PDE5 Inhibitor Avanafil: An Update

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