Computational Prediction of Cassia angustifolia Compounds as a potential Drug Agents against Main Protease of SARS-nCov2

Full Length Research Article

Computational Prediction of Cassia angustifolia Compounds as a potential Drug Agents against Main Protease of SARS-nCov2

Rashid Saif1*, Kanza Ashfaq1, Ghafran Ali1, Ali Iftekhar1, Saeeda Zia2, Muhammad Zubair Yousaf3

Adv. life sci., vol. 9, no. 1, pp. 36-40, May 2022
*- Corresponding Author: Rashid Saif (Email: rashid.saif37@gmail.com)
Authors' Affiliations

 1. Decode Genomics, 323-D, Punjab University Employees Housing Scheme, Lahore – Pakistan
2. Department of Sciences and Humanities, National University of Computer and Emerging Sciences, Lahore- Pakistan
3. Department of Biological Sciences, FCCU, Lahore– Pakistan
 [Date Received: 21/09/2020; Date Revised: 20/02/2022; Date Published: 25/05/2022]

Abstractaa download_button
Introduction
Methods
Results
Discussion
References 

Abstract

Background: In November-December 2019, a plethora of pneumonia like cases were reported in Wuhan, China. After some time, the causative agent of this ailment was identified and named as a novel coronavirus 2. This novel virus spread over the world with no time and declared as pandemic by WHO. To develop antiviral drugs, different clinically used drugs were used as a trial but went in vain. In the current study, we choose an herb with already known therapeutic effects to check its antiviral properties against this virus too.

Methods: Cassia angustifolia is a well-known herb for pharmaceutical industries as its different compounds are already used in different medicines. Here we performed molecular docking of main compounds of Cassia angustifolia against the main protease of SARS-nCoV2 and were compared with different drugs that are already being used on commercial bases to obtain the lowest energy complex. Auto-Dock vina and its packages were used for molecular docking of SARS-nCov2.

Results: Molecular docking of Cassia angustifolia compounds represent very promising binding energies complexes, e.g., Sennoside B gives -9.05kcal/mol and Aloe-Emodin give -4 Kcal/mol of energy against the main protease of coronavirus. In contrast, a couple of commercially used antiviral drugs were also evaluated against the selected protein of coronavirus e.g., Hydroxychloroquine and Ribavirin complexes appeared with -5.2 Kcal/mol and -6.3 Kcal/mol of energy respectively.

Conclusion: Many compounds of Cassia angustifolia showed the promising energy complexes even better than the commercially used antiviral drugs e.g., Sennoside B which has the best energies against main protease of coronavirus. Further, in-vivo and in-vitro studies are needed to validate this hypothesis with advanced MD simulations and wet-lab experimentations.

Keywords: Molecular docking; 6LU7; Auto-Dock Vina; SARS-nCov2 

Introduction6th button-01

Wuhan, the capital city of Hubei Province and the major transportation hub of China started dealing with severe pneumonia with unknown causes in local hospitals at the beginning of December 2019. China informed about the outbreak of this disease to the WHO on December 31st. Most of the patients were exposed to the famous Hunan wholesale sea market of Wuhan. Consequently, Hunan sea market was closed on 1st January [1]. The virus spread rapidly across all over the world. On March 11, WHO announced it as a Pandemic disease. Effective prevention and treatment were essential in this situation. Some of the studies showed the herbal remedies to prevent Coronavirus [2]. Cassia Senna L. (Cassia angustifolia) is a well-known curative herb cultivated in areas near Somalia, Sudan, Arabian Peninsula and upper Nile as well as India and Pakistan. Cassia angustifolia is considered as a medicinal herb due to its therapeutic properties: ⅰ)Anti-Oxidative [3] ⅱ) Anti-Diabetic [4] ⅲ)Anti-obesity [5] ⅳ)Anti-Cancer [3] . The medical importance of Cassia angustifolia has motivated researchers to investigate its therapeutic effect against CoVID19.

In the current study, we report the results of the molecular docking of Cassia angustifolia with the main protease protein of coronavirus. For the comparison of binding energies, commercially available drugs used against the SARS-nCov2 were selected (Hydroxychloroquine, Ribavirin, Favipiravir, Remdesivir) and compared with Cassia angustifolia [6,7]. All of these were selected according to Lipinski’s physiochemical properties.

Methods6th button-01

Curative Herb Choice

On regional review, we stated that Cassia Senna L. (Cassia angustifolia) usually known as Alexandrian Senna, Indian Senna or Senna Makki leaves has been conventionally suggested during the COVID-19 pandemic for their expected antiviral effects. Historically, Senna leaves have been used as early as the 9th century when Arabian physicians treated constipation by using both its leaves and pods.

Selection of Target Protein

The crystal structure of COVID-19’s main protease in complex with an inhibitor N3 (PDB ID: 6LU7) was acquired from Protein Data Bank-RCSB (PDB) (https://www.rcsb.org/). (Table 1)

Molecular Structure and Selection of Ligands

The 2D structure of the ligand Sennoside B and 3D structure of 6-Hydroxymusicin, Tinnevellin Glucoside, Aloe-Emodin, Kaempferol were acquired from PubChem (https://pubchem.ncbi.nlm.nih.gov) [8,9] which were used as a potential drug agent taken from Cassia angustifolia (Figure 2) . There are some other Sennoside compounds available in this Herb which includes Sennoside A, C and D having similar structures to Sennoside B (Figure 1).

All of the compounds selected for Cassia angustifolia were chosen according to Lipinski’s physiochemical parameter rule [10,11] obtained from PubChem. (Table 2)

Commercial drugs were chosen to compare the binding energies with the obtained docking results and their molecular 2D structures were prepared using chem Draw. (Figure 3). The drugs were chosen following the properties of Lipinski’s Physiochemical parameters, which were obtained using PubChem (https://pubchem.ncbi.nlm.nih.gov). (Table 3)

Software/Platform used for Molecular Docking

The tools that were used for protein docking are AutoDock Vina-ADT (version 1.5.7) package [12] and Discover Studio 2020. Different tools were deployed for docking purposes (MGL tool, Python, CADD, Vision).

Preparation of Protein and Ligands

For the preparation of protein receptor, some important steps were carried out. Preliminary query protein molecule was purified using Discovery Studio. Protein sequence was extracted from PDB (ID:6LU7) in the PDB format. Protein sequence was read through the Discovery Studio to visualize and edit protein structure in order to remove the water molecules and other bound ligands. The protein was purified and was saved as a PDB format file.

For the preparation of Ligands, Structure of ligand such as Sennoside B was extracted from PubChem. The 2D/3D structure of the ligand was mined in SDF file. Using Discovery Studio, the structure was visualized and the format of SDF was changed into PDB file format.

Recognition of Active Site

Molecular docking of Main Protease in complex with inhibitor N3 was a blind Docking (Docking without knowing binding and active site) computed using AutoDock Vina. The active site of the protein was designated automatically by the software. In order to make the process more efficient, different tools and references can be used for the conformation of the active site in proteins before docking.

Synchronize Grid Box

After the automated recognition of Active site, polar molecules of hydrogen were added successfully by using MGL Tool. Using the MGL tool to customize the 3D grid box, the number of points were set according to the three dimensions i.e., X, Y and Z (Figure 4). Figure 4 depicts that the number of points in the three dimensions are set to 26 by default, and then spacing (angstrom) is set to be at 1.000 so that it can cover the maximum area of the protein. Centre of grid box for X, Y and Z are set automatically by the tool. After setting of grids, the file was saved in the PDBQT format.

Finalizing Ligand Preparation

For the preparation of ligand, angle of torsion must be defined. Open the ligand file in MGL tool and set the number of torsion angle by default for the fewest atom. Save this file in the PDBQT format. 

Results

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Obtained results shows that Sennoside B has greater energy complex of -9.05 kcal/mol in a result of Docking with Main protease of a coronavirus protein which is considered as best docking score when compared to all other compounds of Cassia angustifolia given in (Table 4). Commercially used drugs have lower energies as compared to the compounds of Cassia angustifolia such as Hydroxychloroquine gives the docking score of -5.2 kcal/mol. Interaction with the other compounds and commercially used drugs docking score is given in the (Table 5).

By using Discovery studio visualize the 2D interaction between the compounds and the main peptidase protein of SARS-nCov2. (Table 8)

 

 

 

Figures & Tables


Discussion6th button-01

On 19 December, the outbreak of a respiratory disease spread in Wuhan, city of China. The spread of this disease occurred by a virus known as SARS-nCov2 and within a month this disease was spread all over the world and on 11th march it was considered as Pandemic. A team of researchers and scientists strongly upheld that a new vaccine or a drug was crucial to fight against the infection. Some of the herbs were also considered as potential drug agents. One of the herb Cassia angustifolia was chosen to study the inhibitory effect against SARS-nCoV2. Diverse compounds of Cassia angustifolia (Sennoside B, 6-Hydroxymusicin, Tinnevellin Glucoside, Aloe-Emodin, and Kaempferol) were selected according to their Lipinski’s physiochemical parameter and their docking results were compared with different commercially used drugs such as Hydroxychloroquine, Ribavirin, Favipiravir, and Remdesivir. Docking results show that the compounds of Cassia angustifolia, Sennoside B - and Aloe-emodin, have the lowest binding energies as compared to the commercially used drugs Ribavirin and Favipiravir.

High throughput drug screening through molecular docking has been recognized as a key technique for in-silico therapeutic design. Our work is important because it can be compared to more comprehensive studies such as the Supercomputer based docking of SARS COV-2 viral spike protein with human ACE2 receptor carried out by the US department of energy. Having screened more than 8000 ligands, the top scoring Vina ligand had a score of -7.4 kcal/mol while Sennoside B in our study had a score of -9.05 kcal/mol. The results therefore show that high throughput screening of natural compounds could lead to more potent therapeutic options, validating the purpose and design of our study.

We conclude our discussion by making instance that the compounds of Cassia angustifolia are more compatible drug agents against the SARS-nCov2 as compared to the scores obtained from the clinically used drugs. This hypothesis still needs more research to validate.

The main purpose of the current study is to use natural herbs as a potential drug agent against the main protease of the novel coronavirus (SARS-COV2) infection. Results obtained by molecular docking showed that Cassia angustifolia and its compounds Sennoside B and Aloe-emodin have the lowest binding energies when compared to the commercial drugs of Hydroxychloroquine and Favipiravir. Hence, we can consider that Cassia angustifolia having Sennoside B and Aloe-emodin may have the potential to act as an antiviral drug against this pandemic. However, further in-vitro and in-vivo studies are still needed to validate this hypothesis, postulated through this initial computer aided prediction of the aforementioned compounds as potential drug agents.

Author Contributions

(RS) envisaged the idea, involved in critical thinking, analysis of data, editing, proofread and correspondence with journal. (KA), (GA) and (AI) helped in data analysis, initial write-up and composing, (SZ) helped in understanding the statistics behind the used software and comparing their algorithms for better hits, (MZY) helped in critical thinking and proof reading the manuscript.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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