In silico screening of purarin derivatives for the treatment of covid-19 Shivam Chauhan, and Mani Srivastava* School of life science, SIILAS Campus, Jaipur National University, Jaipur E-mail: shivamchauhan5120420@gmail.com
Abstract The COVID-19 (coronavirus disease 2019) was reported in China during December 2019. It has spread on a global scale. While novel vaccines and drugs that target SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) are under development. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Consumption of bioactive compounds from natural products considered to be beneficial and safe for inhibit viral replication cycles become an essential source of safe and effective antiviral drugs and may be beneficial for future viral pandemics when standard treatments are unavailable. Puerarin is an class of Isofavonoid from Pueraria tuberculosa which can be a possible inhibitor of the angiotensin-converting enzyme-2 (ACE2). In our study of in-silico analysis of Puerarin derivative revealed high binding affinity with the target. In our In-Silico drug designing study the rapid Protein-Ligand Docking was performed by using with software AutoDock 4.0. In-silico ADMET prediction has been done to calculation of drug likeliness and correlating physicochemical properties of Puerarin derivatives with its biological activity. ADMET optimization and screening of lead allow us to conclude Puerarin derivatives to be used for future treatments against COVID-19 with the specific benefits without adverse effect. Keywords- AutoDOCK, puerarin, SARS-CoV-2.
Results
•T
Docking with Main Protease (6LU7)
Erythgianin A
-8.0
Docking with spike protein (6LZG) Erythgianin A
-9.6
Introduction
In case of COVID-19,the viral acess is mediated by the binds to a host cell recepoter, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) of its envelope (spike S) glycoprotein .Therefore ACE2 has been an agreeable target for COVID-19 infection.Reports suggested that viral infection inhibited by blocking ACE2 since viral spike can’t bind with it.Reporter suggested that natural phytochemical from a medical herb like withania somnifera have distinct effective antiviral, along with the strategy followed in the present work. Puerarin is an class of Isofavonoid from Pueraria tuberculosa which can be a possible inhibitor of antiotensin-converting enzyme-2(ACE2). Pueraria tuberosa also known as vidarikanda which is a perennial herb throughout south east Asia. The bioactive compound of pueraria is also puerarin.Puerarin also reported for porcine epidemic diarrhea virus.Consumption of bioactive cpmpounds from natural products considered to benefical and safe for inhibit viral replication cycle become an essential source of safe and effective antuviral drugs and may be beneficial for future viral pandimics when standard treatments are unavailable.They are cheap, easily produced and right candidate for interest.Repositioning phytocompounds model in drug desining will accelerate process. In our study of in-silico analysis of Puerarin derivative revealed high binding affinity with ACE2.
ARG-131,THR 199,LYS137,ASP-289,LEU-287
ALA-348,ASP-382,ARG393,TYR-385,HIS-401
Drug likeliness Ligan ds
MW
LOG P
HBA
HBD
TPS A
AMR
RB
Eryth gianin A
386. 35
2.27
5
8
140. 59
99.2 5
2
ADMET GI absorption
BBB permeant
CYP450 inhibitor
Carcinogenicit y
High
No
NO
Non
6LU7
6LZG Conclusions
.
Methods
For experimental work we utilizes online available software’s Chemsketch for drawing analogues of Puerarin Autodock for Docking Studies (SBDD) in the form Binding affinity of target Protein & Ligand Molecule. OSIRIS Property Explorer: For the calculation of ADMET properties (LBDD) according to Lipinsky rule of five.[ Lipinski, 2001] . Docking methodology: Chemsketch 11 Ligand preparation (AutoDOCK) Geometry minimisation Target protein extracted from PDB Optimisation Protein preparation (AutoDOCK) Docking by AutoDOCK
Ligand preparation
Target - protein preparation DOCKING (AutoDOCK)
Docking score Binding affinity
Out of 68 candidates Erythgianin-A bind with a higher binding affinity and least binding energy with spike receptor-binding domain complexed with its receptor ACE2, has a binding energy of -9.6 kcal/ mol, associates with 6 hydrogen bond with ALA-348,ASP-382,ARG393,TYR-385,HIS-401. Thus indicating thatpuerarin has a better inhibitory property against SARS-CoV-2. Puerarin revealed exceptional druggability properties which is confirm as a result of its molar refractivity which indicates the its ability to pass through specific biomembranes amid weak or strong interactions. Furthermore, the lipophilicity of puerarin reveals its characteristics for oral absorption. The ADME data, predicted that puerarin had no significant ADME properties thatcan lead to serious side effects in humans.Puerarin is also not mutagen neither carcinogenic as in this study docking has been done by using AUTODOCK. Despite of significant interaction Puerarine and its derivatives showed significant levels of toxicity and bioaccumulation hence it cannot be used as a pharmaceutical product unless it is made into a pro-drug. References 1.Prabakaran P, Gan J, Feng Y, Zhu Z, Choudhry V, Xiao X, Ji X, Dimitrov DS. Structure of severe acute respiratory syndrome coronavirus receptor-binding domain Complexed with neutralizing antibody. Journal of Biological Chemistry. 2006 Jun9;281(23):15829- 36. 2.Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG. Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. Journal of virology. 2013 Jul 15;87(14):8017-28. 3.Dau B, Holodniy M. Novel Targets for antiretroviral therapy. Drugs. 2009 Jan1;69(1):31-50. 4.nand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science. 2003 Jun 13;300(5626):1763-7. 5.Structural and molecular basis of angiotensin-converting enzyme by computational modeling: Insights into the mechanisms of different inhibitors Li Fang 1,2 , Mingxian Geng 1,2,3 , Chunlei Liu 1,2 , Ji Wang 1,2 , Weihong Min ID 1,2 *,Jingsheng Liu 1,2 6.Novel Coronavirus (SARS-CoV-2) Main Protease: Molecular docking of Puerarin as a Potential inhibitor Landmark University, Omu-Aran, Nigeria