Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Scaffold hopping strategy on the route discerning novel Glutathione peroxidase agonists

Alzheimer’s disease (AD), the utmost common and progressive neurodegenerative disease characterized by aggregation of β-amyloid plaques triggered by mitochondrial oxidative stress also. Raising substantial evidences evokes that diluted antioxidant activity correlates with overproduction of free radicals and peroxides. Which extends the alterations in membrane permeability damaging the mitochondrial respiratory chain, subsequently amplifying the neuronal dysfunction there by triggering neurodegeneration. Glutathione peroxidases (GPx1-2) is abundant antioxidant enzyme that catalyze reduction of hydrogen peroxide to water. Increased free radicals and absurdity in potentiality to detoxify the reactive intermediates associated with diluted activity of GPx has made it as a possible attractive therapeutic target for AD intervention. Five existing agonists were subjected to geometry based virtual screening against in-house library having more than 21 million small molecules. The resulted 1273 hits were subjected to rigid receptor docking (RRD) and quantum polarized ligand docking (QPLD) succeeded with binding free energy (∆G) calculations, resulted best ligands (2 for GPx1 and 1 for GPx2). The best ligands and existing agonists were subjected to scaffold hopping against fragment libraries resulted 644 compounds, which are subjected to multi-level multiple docking strategies to derive the best leads (12 for GPx1; 14 for GPx2) with favorable pharmacokinetic properties (fig.1). Further, GPx and the best lead complexes were subjected to 50ns MD simulations to analyze the stability (fig.2) as well as the intactness (fig.3) of the best leads towards the receptor. The proposed leads, obtained from scaffold hopping of existing agonists showed favorable binding orientation with increased binding affinity towards GPx, by enhancing the sulfhydryl groups availability to ROS and peroxide intermediates ensures the anti-oxidant activity. The intensifying GPx levels with the proposed leads enriches the anti-oxidant effect. Thus, the results emphasis that the proposed novel leads would be effective in treating oxidative stress mediated AD therapeutics.



    Natarajan P, Priyadarshini V, Pradhan D, Manne M, Swargam S, Kanipakam H, et al. (2016) E-pharmacophore-based virtual screening to identify GSK-3β inhibitors. J Recept Signal Transduct 36(5):445–458.

    Wang L, Deng Y, Wu Y, Kim B, LeBard DN, Wandschneider D, et al. (2017) Accurate Modeling of Scaffold Hopping Transformations in Drug Discovery. J Chem Theory Comput 13(1):42–54.

    Pradeep N, Munikumar M, Swargam S, Hema K, Sudheer Kumar K, Umamaheswari A. (2015) 197 Combination of e-pharmacophore modeling, multiple docking strategies and molecular dynamic simulations to discover of novel antagonists of BACE1. J Biomol Struct Dyn 33 Suppl 1:129–130.

Natarajan Pradeep 1
Katari Sudheer Kumar2
Amineni Umamaheswari2
Manne Munikumar3
Sandeep Swargam4
Kanipakam Hema5
Praveen Kumar Guttula6 and
Mukesh Kumar Gupta6

1,6Bioinformatics Centre, Department of Biotechnology & Medical Engineering, National Institute of Technology, Rourkela, Odisha, India - 769008.

2Bioinformatics Centre, Department of Bioinformatics, Sri Venkateswara Institute of Medical Science University, Tirupati, Andhra Pradesh, India – 517507.

3NIN-TATA Centre for Excellence in Public Health Nutrition, ICMR-National Institute of Nutrition, Jamai-Osmania (Post), Hyderabad, Telangana, India-500007.

4Jamia Hamdard Institute of Molecular Medicine, Jamia Hamdard University, Hamdard Nagar, New Delhi, India-110062.

5Functional genomics unit, CSIR-IGIB, New Delhi, India-110007.

Ph: +91-9949442837
Email: drpradeepnatarajan@gmail.com