Premkumar Jayaraj1, Chandrakala A Narasimhulu2, Andrei Maiseyeu3, Rekha Durairaj3, Shashidhar Rao4, Sanjay Rajagopalan3, Sampath Parthasarathy2, Rajagopal Desikan5,2,1. 1. Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore 632014, India. 2. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA. 3. Cardiovascular Research Institute, Case Western Reserve University, School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA. 4. Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, NJ 08554, USA. 5. Carmel Biosciences, 3562 Habersham at Northlake, Building J, Suite A, Tucker, GA 30084, USA.
Abstract
Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results: In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 μM and -8.35 kcal/mol, 8.5 μM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.
Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results: In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 μM and -8.35 kcal/mol, 8.5 μM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.
Authors: Snehal U Naik; Xun Wang; Jaqueline S Da Silva; Michael Jaye; Colin H Macphee; Muredach P Reilly; Jeffrey T Billheimer; George H Rothblat; Daniel J Rader Journal: Circulation Date: 2005-12-19 Impact factor: 29.690
Authors: S L Hazen; R Zhang; Z Shen; W Wu; E A Podrez; J C MacPherson; D Schmitt; S N Mitra; C Mukhopadhyay; Y Chen; P A Cohen; H F Hoff; H M Abu-Soud Journal: Circ Res Date: 1999-11-12 Impact factor: 17.367