Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone-derived aryl thioureas with
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ORIGINAL ARTICLE
Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone‑derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR and kinetic profiling Asma Khurshid1 · Aamer Saeed1 · Zaman Ashraf2 · Qamar Abbas3 · Mubashir Hassan4 Received: 9 May 2020 / Accepted: 19 August 2020 © Springer Nature Switzerland AG 2020
Abstract The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a–l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a–l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing I C50 value 0.420 ± 0.012 µM, many folds better than reference standard used (KH2PO4 IC50 = 2.8 ± 0.06 µM and l-phenylalanine IC50 = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed noncompetitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a–l.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10136-9) contains supplementary material, which is available to authorized users. * Asma Khurshid [email protected] * Aamer Saeed [email protected] 1
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
2
Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan
3
Department of Physiology, University of Sindh, Jamshoro, Pakistan
4
Department of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
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Vol.:(0123456789)
Molecular Diversity
Graphic abstract
Keywords Aminophenazone · Intestinal alkaline phosphatase · Non-competitive inhibition · RO5 validation
Introduction Alkaline phosphatase is a subdivision of the major class of ectoenzymes named as ectonucleotidases. These ectoenzymes are mainly involved in hydrolysis of extracellular nucleotides to nucleosides and adenosine via direct or indirect pathways. Alkaline phosphatases are found on the outer surface of plasma membrane and are responsible for catalyzing the hydrolysis of phosphate groups from a variety of different substrates (dephosphorylation) in an alkaline environment, freeing inorganic phosphate (Pi) [1, 2]. In addition to this, APs also mediate the hydrolysis of a variety of substrates other than nucleotides, such as bis(p-nitrophenyl) phosphate, inorganic polyphosp
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