Vishvakarma VK, et al., J Protein Res Bioinform 2020, 2: 005
HSOA Journal of Protein Research and Bioinformatics Research Article
A Model to Study the Inhibition of Arginase II with Noscapine & Its Derivatives Vijay Kumar Vishvakarma1,2, Prashant Singh1* and Kamlesh Kumari3# Department of Chemistry, Atma Ram Sanatan Dharma (ARSD) College, University of Delhi, New Delhi, India
1
2
Department of Chemistry, University of Delhi, New Delhi, India
Department of Zoology, Deen Dayal Upadhyaya (DDU) College, University of Delhi, Dwarka, Delhi, India
3
#
Equal Contribution
Abstract Background and Purpose: Nitrate tolerance can be explained based on the reduction of the vessel responsiveness and the same is used for endogenous vasodilator Nitric Oxide (NO). There are some limitations for the treatment of ischaemia, angina etc. and it attracted the scientists and researchers. The location of arginase II is endothelial cells in mitochondria and it is used to change the potency of endothelial nitric oxide synthase. Experimental approach: A theoretical model has been developed to find the potent arginase II inhibitor. A library of noscapine (116 molecules) was designed and optimized using computational tools. Then, the designed molecules were docked with the arginase II (PDB: 4IXU) using iGemdock. Based on binding energy, the potential candidate was screened. Further, absorption distribution metabolism, excretion and toxicity (ADMET) using online web-server and density functional theory (DFT) study of the top four screened molecule has been studied by using Gaussian. Then, molecular dynamic simulation of arginase II with and without 97 was performed using Gromacs. Further, the binding energy was determined using MM-PBSA on Gromacs. Conclusion: Compound no.97 showed the best binding with the arginase II based on docking. Further, the potency of the screened noscapine 97 against arginase II was compared with the reported molecules. MD simulations showed the stable anchoring of the argi-
*Corresponding author: Prashant Singh, Department of Chemistry, Atma Ram Sanatan Dharma (ARSD) College, University of Delhi, New Delhi, India, Tel: +91 1124113436; E-mail: psingh@arsd.du.ac.in Citation: Vishvakarma VK, Singh P, Kumari K (2020) A model to study the inhibition of Arginase II with Noscapine & its derivatives. J Protein Res Bioinform 2: 005. Received: January 07, 2020; Accepted: April 18, 2020; Published: April 24, 2020
Copyright: Š 2020 Vishvakarma VK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
nase II-97 complex and the binding energy between 97 and arginase II was found to be negative i.e. -815.184 kcal/mol. Keywords: Density functional theory; MM-PBSA; Molecular dynamics simulation, Noscapine; Protein data bank.
Introduction Angina pectoris is an uncomfortable condition, like chest pain and it is due to less oxygen supply to the coronary artery [1,2]. The endothelium plays a fundamental role in the regulation of the thrombotic process by releasing Endothelial-derived Relaxing Factor (EDRF) [3]. The major compound Nitric oxide (NO) regulates the arterial pressure by dilating the blood vessels [4]. NO is synthesized from arginine by means of endothelial Nitric Oxide Synthase (eNOS) [5]. Many research groups have focused to develop the bioactive compounds to alter the L-arginine metabolism in the body. Arginase-II catalyzes the degradation of arginine into ornithine and urea [6]. Arginase-II is responsible for the bioavailability of L-arginine for Nitric oxide synthase (NOS) by the mean of the competition of substrate [7]. Therefore, when the activity of arginase is increased, it causes diseases by reducing the amount of L-arginine in the body. It is needed by NOS to produce NOe [6-8]. In the last few decades, researchers showed great interest in studying the role of arginase in the cure of diseases. Various arginase inhibitors have been reported and have shown potential under different pathophysiological conditions like renal injury in diabetic [9], atherosclerosis [10], erectile dysfunction and pulmonary hypertension [11,12], hypertension [13], allergic rhinitis [14] and many more. Phthalideisoquinilines based alkaloids are popular molecules and cones under the class of isoquinoline based compounds viz. erythro and threo form. Noscapine contains isoquinoline and benzofuran ring as an active ingredient. Primarily it is used as an antitussive agent to suppress a cough. At present, noscapine its its derivatives are explored and under clinical trials for the treatment of different diseases like cancer [15,16]. There is too much structural variability in noscapine, which make its use for different purposes. Considering that the development of arginase-II inhibitors is of great therapeutic relevance to cure angina. The potential of the erythro form of noscapine against the arginase-II has been investigated. In the present work, a theoretical model for the inhibition of arginase-II by noscapine and its derivatives was developed. Molecular docking, density functional theory, Absorption distribution metabolism, excretion and toxicity (ADMET), Molecular dynamic (MD) simulations along with Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis were performed to find the potent arginage II inhibitor.
Experimental This experimental work is categorized into five parts i.e. designing of molecules & molecular docking, ADMET studies, DFT studies, MD simulations along with MM-PBSA analysis. The overall experimental approach of the work can be understood by flowchart 1.