title: Exploring the binding mechanism and kinetics of Piperine with snake venom secretory Phospholipase A2.
abstract: Secreted venom Phospholipase A2is highly responsible for pharmacological effects like neurotoxicity, myotoxicity, hemolytic, anti-coagulation, and platelet aggregation. Neutralization of these pharmacological behaviors is one of the challenges existing for many decades and a potent drug compound for this is very much needed to control local effects of venom sPLA2. In this study, we investigated binding mechanism and kinetics of inhibition of Piperine (major constitute of Piper nigrum) with sPLA2using DFT, MD simulation, MM-PBSA, and SPR method. Frontier MO properties were suggested that it procured better chemical reactivity and druglikeness and binding mode of Piperine with EcPLA2defined that it occupied well in N-terminal hydrophobic cleft. The persistence of Piperine interactions with and without calcium ion was analyzed and confirmed by MD simulation analysis. The dPCA-based FEL shows the nature of apo- and Piperine-bound conformational behavior of EcPLA2including intermediate forms. Further, binding energy of Piperine was calculated by high-throughput MM-PBSA which states that calcium ion presence enhances the Piperine binding by additional electrostatic interactions. Finally, kinetics of inhibition between Piperine and EcPLA2implied that it secured better binding affinity (KD: as 1.708 pM) and the result gives clear evidence for the binding mechanism and binding energy calculated. In conclusion, Piperine was authenticated with better drug ability, entrenched binding interaction, and robust kinetics of inhibition with EcPLA2through which it can become an exceeding drug candidate for pharmacological as well as catalytic activity of sPLA2.
authors.affiliation: a Centre for Bioinformatics, Pondicherry University , Pondicherry , 605014 , India.
authors.forename: A
authors.initials: A
authors.lastname: Christian Bharathi
authors.affiliation: b GE Healthcare Life Sciences, John F Welch Technology Centre , EPIP, Phase 2, Whitefield Road, Bangalore , 560048 , India.
authors.forename: Sistla
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: a Centre for Bioinformatics, Pondicherry University , Pondicherry , 605014 , India.
authors.forename: B
authors.initials: B
authors.lastname: Syed Ibrahim
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D012910:Snake Venoms / Q000201:enzymology*; D020349:Surface Plasmon Resonance
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D012910:Snake Venoms; D054497:Phospholipases A2, Secretory; C008922:piperine
keywords: DFT; Piper nigrum; dPCA and SPR; frontier MO