Vishvakarma VK, et al., J Protein Res Bioinform 2020, 2: 008 DOI: 10.24966/PRB-1545/100008 HSOA Journal of Protein Research and Bioinformatics Research Article nase II-97 complex and the binding energy between 97 and arginase A Model to Study the Inhibition II was found to be negative i.e. -815.184 kcal/mol. of Arginase II with Noscapine & Keywords: Density functional theory; MM-PBSA; Molecular dynam- Its Derivatives ics simulation, Noscapine; Protein data bank. Introduction Vijay Kumar Vishvakarma1,2, Prashant Singh1* and Kamlesh Kumari3# Angina pectoris is an uncomfortable condition, like chest pain and it is due to less oxygen supply to the coronary artery [1,2]. Endothe- 1Department of Chemistry, Atma Ram Sanatan Dharma (ARSD) College, lium has an important role in deciding the role in the release of En- University of Delhi, New Delhi, India dothelial-Derived Relaxing Factor (EDRF) [3]. The major compound 2Department of Chemistry, University of Delhi, New Delhi, India Nitric oxide (NO) regulates the arterial pressure by dilating the blood vessels [4]. NO is synthesized from arginine by means of endothe- 3 Department of Zoology, Deen Dayal Upadhyaya (DDU) College, University of lial Nitric Oxide Synthase (eNOS) [5]. Many research groups have Delhi, Dwarka, Delhi, India focused to develop the bioactive compounds to alter the L-arginine #Equal Contribution metabolism in the body. Arginase-II catalyzes the degradation of arginine into ornithine and urea [6]. Arginase-II is responsible for the bioavailability of Abstract L-arginine for Nitric oxide synthase (NOS) by the mean of the com- Background and Purpose: Nitrate tolerance can be explained petition of substrate [7]. Therefore, when the activity of arginase is based on the reduction of the vessel responsiveness and the same increased, it causes diseases by reducing the amount of L-arginine is used for endogenous vasodilator Nitric Oxide (NO). There are in the body. It is needed by NOS to produce NOe [6-8]. In the last some limitations for the treatment of ischaemia, angina etc. and it few decades, researchers showed great interest in studying the role of attracted the scientists and researchers. The location of arginase II is arginase in the cure of diseases. Various arginase inhibitors have been endothelial cells in mitochondria and it is used to change the potency of endothelial nitric oxide synthase. reported and have shown potential under different pathophysiological conditions like renal injury in diabetic [9], atherosclerosis [10], erec- Experimental approach: A theoretical model has been developed tile dysfunction and pulmonary hypertension [11,12], hypertension to find the potent arginase II inhibitor. A library of noscapine (116 [13], allergic rhinitis [14] and many more. molecules) was designed and optimized using computational tools. Then, the designed molecules were docked with the arginase II Phthalideisoquinilines based alkaloids are popular molecules and (PDB: 4IXU) using iGemdock. Based on binding energy, the poten- cones under the class of isoquinoline based compounds viz. erythro tial candidate was screened. Further, absorption distribution me- and threo form. Noscapine contains isoquinoline and benzofuran ring tabolism, excretion and toxicity (ADMET) using online web-server as an active ingredient. Primarily it is used as an antitussive agent and density functional theory (DFT) study of the top four screened molecule has been studied by using Gaussian. Then, molecular dy- to suppress a cough. At present, noscapine its its derivatives are ex- namic simulation of arginase II with and without 97 was performed plored and under clinical trials for the treatment of different diseases using Gromacs. Further, the binding energy was determined using like cancer [15,16]. There is too much structural variability in noscap- MM-PBSA on Gromacs. ine, which make its use for different purposes. Conclusion: Compound no.97 showed the best binding with the There is need to find the arginase II inhibitor to control or cure an- arginase II based on docking. Further, the potency of the screened gina. The potential of the erythro form of noscapine against the argin- noscapine 97 against arginase II was compared with the reported ase-II has been investigated. In the present work, a theoretical model molecules. MD simulations showed the stable anchoring of the argi- for the inhibition of arginase-II by noscapine and its derivatives was developed. Molecular docking, density functional theory, Absorption *Corresponding author: Prashant Singh, Department of Chemistry, Atma Ram distribution metabolism, excretion and toxicity (ADMET), Molecular Sanatan Dharma (ARSD) College, University of Delhi, New Delhi, India, Tel: +91 1124113436; E-mail: [email protected] dynamic (MD) simulations along with Molecular mechanics Pois- son–Boltzmann surface area (MM-PBSA) analysis were performed Citation: Vishvakarma VK, Singh P, Kumari K (2020) A model to study the in- to find the potent arginage II inhibitor. hibition of Arginase II with Noscapine & its derivatives. J Protein Res Bioinform 2: 008. Experimental Received: January 07, 2020; Accepted: April 18, 2020; Published: April 24, 2020 This experimental work is categorized into five parts i.e. designing Copyright: © 2020 Vishvakarma VK, et al. This is an open-access article of molecules & molecular docking, ADMET studies, DFT studies, distributed under the terms of the Creative Commons Attribution License, which MD simulations along with MM-PBSA analysis. The overall experi- permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. mental approach of the work can be understood by flowchart 1. 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: 008. • Page 2 of 14 • Designing of molecules and molecular docking EBinding = EVDW + Hbond + Elec (1) Designing of molecules VDW - vander Waal energy; H - hydrogen bonding energy; There are two isomeric form of noscapine viz., erythro and threo bond form. Herein, only erythro-form of noscapine was considered due to Elec - electro statistic energy its high stability and biological potential. In the present work, a total The modelling of the docked poses is studied by Discovery studio of 116 molecules based on noscapine were designed as in table 1. visualizer v 3.5 [18]. ADMET properties The ADME (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties were calculated to check the better bioavail- ability of the proposed drug molecule. Physicochemical parameters The physiochemical properties like Log S, Solubility, number of heavy atoms, number of rotatable bonds, number H-bond acceptors, number H-bond donors, Log Po/w, and physiochemical space for oral availability were checked by the web server (http://www.swissadme. ch/) [19]. Biological properties The biological properties like TPSA (Ų), GI absorption, BBB per- meant, P-gp substrate, and CYP3A4 inhibitor were calculated by the web server (http://www.swissadme.ch/). Absorption (% ABS) of top four molecules was calculated according to the method described by Zhao et al. [20] TPSA is an important factor to give an idea for ability of drug transport and can be determined by using equation 2. The results are incorporated in table 4. Flowchart 1: The overall methodologies used in the whole work. %ABS = 109 – [0.345 × topological polar surface area (TPSA) (2) Geometry optimization of noscapines & reported molecules Other biological properties like GPCR ligand, ion channel mod- The designing of all compounds were done by using ACD ulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor, Chemsketch and their optimization was done by choosing molecular and enzyme inhibitor value by using the online server molinspiration mechanics (MM2) as a force field. These optimized compounds were (www.molinspiration.com) [21]. used for docking. Toxicity Protein preparation The acute rat toxicity of the top four molecules was calculated Protein preparation was done by using Molegro Molecular Viewer using an online server GUSAR (http://www.way2drug.com/gusar/ (MMV 2.5). The following parameters were checked like flexible tor- acutoxpredict.html). The toxicity parameters like IP LD50, IV LD50, sion in compounds, missing charges, assigning of bonds, tripos type atoms and missing explicit hydrogen. The prepared protein was used Oral LD50, and SC LD50 for all four route of administration i.e., oral, for the docking analysis and MD simulation. intraperitoneal, intravenous, and subcutaneous for top four molecules were calculated. This toxicity model was based on a rat [22]. Molecular docking DFT analysis The docking of all noscapines (Table 1) and the reported mole- cules (Table 2) was performed using iGemdock [17] against the argi- Density functional theory (DFT) have been performed to study nase-II (PDB ID - 4IXV). This software used the generic algorithms the electrical properties of the noscapine derivative. Geometry op- for the docking. timization of the molecules were performed. Becke’s 3 parameters Docking parameters & Post Docking modeling functional Lee, Yang, Parr B3LYP/6-311++G (d, p) was used for the calculation with the Gaussian 09 [23]. Herein, the parameters for the docking are set with population size of 200 and generation of 70 along with two solutions for each. On In addition, DFT is very useful in providing chemical descriptors the basis of the above