my research on molecular docking of antiviral drug to CORONA VIRUS targeted docking structure

Molecular Docking Studies on Angiotensin converting enzyme Antiviral Drugs for SARS COVID_19


INTRODUCTION:

Coronavirus diseases _ 19 is a respiratory disease in humans which is caused by the SARS coronavirus. The treatment of coronavirus-associated Covid _ 19 has been evolving and so far there is no consensus on an optimal regimen. The mainstream therapeutic interventions for SARS involve broad-spectrum antibiotics and supportive care, as well as antiviral agents and immunomodulatory therapy. The Protein-Ligand interaction plays a significant role in structural based drug designing. In the present work, receptor Angiotensin converting enzyme 2 (ACE-2) was docked with drugs that are commonly used against SARS and the energy value obtained is as follows: Lopinavir (-55.81), Ritonavir (-46.95), Depending on the least energy value the best two drugs out of the four conventional drugs have been chosen and tried to improve the binding efficiency and steric compatibility of those two drugs namely Ritonavir and Lopinavir. Several modifications were made to the probable functional groups (phenylic, ketonic groups in case of Ritonavir and carboxylic groups in case of Lopinavir respectively) which were interacting with the receptor molecule. Analogs were prepared by Discovery Studio software and were docked using Chimera docking software. Lopinavir analog 3 and Ritonavir analog 4 were detected with significant energy values and is probable lead molecule. Some of the modified drug analogs are better than the original drugs. Further work can be carried out to improve the steric compatibility of the drug based upon the work done above for a more energy efficient binding of the drugs to the receptor. .


THEORY :

Corona virus diseases or COVID _ 19 is a respiratory disease in human. According to the WHO report [7], there was a major epidemic between November 2019 and present , with a mortality rate of 3.46%. The coronavirus diseases, sometimes shortened to SARS-CoV, is the virus that causative agent of this disease.


A 2006 systematic review of all the studies done on the 2003 SARS epidemic found no evidence that antivirals, steroids or other therapies helped patients. A few suggested they caused harm. [6] The clinical treatment of COVID _ 19 has been relatively ineffective with most high risk patients requiring artificial ventilation. Corticosteroids and Ribavirin and anti malarial hydroxyl choloro quinone are the most common drugs used for treatment of COVID _ 19 .

The administration of corticosteroids, marketed as Prednisone, during viral infections has been controversial. Lymphopenia can also be a side effect of corticosteroids even further decreasing the immune response and allowing a spike in the viral load; yet physicians must balance the need for the anti- inflammatory treatment of corticosteroids [5]

The treatment of coronavirus-associated diseases has been evolving and so far there is no consensus on an optimal regimen. The mainstream therapeutic interventions for COVID _ 19 involve broad-spectrum antibiotics and supportive care, as well as antiviral agents and immunomodulatory therapy. In majority of the cases protease inhibitors like Lopinavir-ritonavir co-formulation is normally used to treat. Preliminary analysis suggests that the addition of lopinavir-ritonavir to the contemporary use of ribavirin and corticosteroids might reduce incubation and mortality rates, especially when administered early, but the survival rate of the patients is low. [1] To overcome these problems people made efforts in non conventional methods of drug designing by the use of Bioinformatics and computer aided softwares Fig 1 : SARS coronavirus _ 19 Fig 2 : thermal map of covid _19

Fig 3 : angio tensin converting enzyme 2 structure selected as docking site :

BIOINFORMATICS:

Bioinformatics is seen as an emerging field with the potential to significantly improve how drugs are found, brought to the clinical trials and eventually released to the marketplace. Bioinformatics can be thought of as a central hub that unites several disciplines and methodologies. Computer–Aided Drug Design (CADD) is a specialized discipline that uses computational methods to simulate drug–receptor interactions.

CADD methods are heavily dependent on bioinformatics tools, applications and databases. As such, there is considerable overlap in CADD research and bioinformatics. Methods developed to facilitate and speedup the drug designing process are Rational Drug Design (RDD). These processes are used in biopharmaceutical industry to discover and develop new drugs. RDD uses a variety of computational methods to identify novel compounds. One of those methods is docking of drug molecules with receptors. The site of drug action, which is ultimately responsible for the pharmaceutical affect, is a receptor.

Angiotensin Converting Enzyme (ACE) [Fig. 3 ] is a receptor, which is an essential regulator of cardiac function and facilitates the entry of SARS-CoV into the cell by serving as its primary receptor. It has two isoforms with 43% homology. It is responsible for initiation of viral infection. In normal practice the conventional drugs like Ribavirin, Ritonavir, Lopinavir are used inhibit viral infection, which are specific to ACE [19].

Keeping rational drug designing approach in mind, We made an effort to design modified drugs for SARS, using conventional drugs like Lopinavir and Ritonavir by docking against ACE-2 receptor. Docking is the process of fitting together of two molecules in 3-dimensional space. Docking allows the scientist to virtually screen a database of compounds and predict the strongest binders based on various scoring functions. It explores ways in which two molecules, such as drugs and an enzyme receptor ACE-2 fit together and dock to each other well, like pieces of a three-dimensional jigsaw puzzle. The molecules binding to a receptor, inhibit its function, and thus act as drug. The collection of Lopinavir, Ritonavir and ACE-2 receptor complexes was identified via docking and their relative stabilities were evaluated using molecular dynamics and their binding affinities, using free energy simulations.


MATERIALS AND METHODS For the present study bioinformatics online databases and software like Discovery studio and Hex docking were used. The databases and software used are as follows: 1. PubMed: PubMed[2], developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM). The database is designed to provide access to citations from biomedical journals. From PubMed we have collected literatures on SARS, receptors and antiviral drugs. Based on the literature, the present study was confined to ACE-2 receptor and the analogs of conventional drugs like Lopinavir and Ritonavir. 2. PDB: The structure of Angiotensin converting enzyme 2 (ACE-2) was retrieved from Protein data bank (PDB). [3] PDB is a repository for the processing and distribution of 3D- structure data of large molecules of proteins and nucleic acids. Most were determined by X-ray crystallography and some by NMR. The structures of conventional drugs like Lopinavir and Ritonavir were also retrieved from PDB 3. RASMOL: The retrieved structure of ACE-2 was analyzed by using RasMol. RASMOL [Raster Display of Molecules] is a molecular graphics program intended for the structural visualizationof proteins, nucleic acids &small biomolecules. RasMol runs on wide range of architectures and operating systems. The program reads the molecule coordinate file and interactively displays the molecule on the screen in a variety of color schemes and molecular representations. 4. Discovery Studio: The structures of conventional drugs like Lopinavir and Ritonavir were retrieved from PDB and the structural analogs of these drug molecules were created by using Discovery Studio. Discovery Studio is a suite of life science software solutions including tools for protein, ligand, and pharmacophore modeling. 5. Chimera molecular docking : Chimera software works on preparation of ligand and protein binding structures and also analyse tensions and hydrogen bonds , hydrophobic interactions , van der waal interaction , it also have tool auto dock vina for auto docking function . RESULTS Docking results between ACE-2 and the conventional drug Lopinavir (Table I) as well as with the modified drugs are tabulated in Table 1. Table 1: Docking Results of ACE-2 With Lopinavir Analogs Drug docked E-value Lopinavir -55.81 Lopinavir Analog 1 -57.98 Lopinavir Analog 2 -47.77 Lopinavir Analog 3 -59.84 Lopinavir Analog 4 -55.39 Lopinavir Analog 5 -59.28 The Structure of the conventional drug Lopinavir as well as the Modified drug is shown in Fig 4 and 5 respectively. Fig.4: Lopinavir-Structure

Fig.5: Lopinavir Analog 3-Structure

Docking results tabulated between Angiotensin converting enzyme-2 and the conventional drug Ritonavir (Table 2 ) as well as the modified drugs are shown below along with the changes or modifications within them. Table 2: Docking Results of ACE-2 With Ritanovir Analogs

Drug docked E-value Ritonavir -46.95 Ritonavir Analog 1 -53.41 Ritonavir Analog 2 -57.67 Ritonavir Analog 3 -37.46

Ritonavir Analog 4 -74.40 Ritonavir Analog 5 -56.16 The Structure of the conventional drug Lopinavir as well as the Modified drug is shown in

Fig 8 and 9


respective


DISCUSSION According to a recent study, [8] it has been shown clearly that the drugs Lopinavir and Ritonavir have been used to target receptor ACE-2. Lopinavir and Ritonavir on docking with ACE-2 produced an energy value of -55.81 and -46.95 respectively. It was observed using RasMol that the carbonyl group present in the drug lopinavir was the site of binding to the receptor (ACE-2) and phenylic and a kenotic functional groups present in the Ritonavir was the site of binding to the receptor (ACE-2) Several modifications were made to these probable functional groups, which resulted in a decrease in the energy values. These modifications were made using Discovery Studio and the energy values were calculated using Hex. This way the pharmacophoric part of the drug was partially identified. An analog (Lopinavir analog 3) was prepared virtually using Discovery Studio. This particular analog showed an increase in the energy values (-59.84) and an analog with additional functional group (Ritanovir Analog 4) was prepared virtually using Discovery Studio. This particular analog showed an increase in the energy values (-74.40) which means the analog (Lopinavir analog 3) and (Ritanovir Analog 4) was more compatible with the receptor than its Analog predecessor. However, the binding site of the analog was similar to that of its predecessor, which means that functional groups involved were the same and by preparing the analog only the steric compatibility was increased. Molecular interactions including protein-protein, enzyme-substrate, protein-nucleic acid, drug-protein, and drug-nucleic acid play important roles in many essential biological processes, such as signal transduction, transport, cell regulation, gene expression control, enzyme inhibition, antibody–antigen recognition, and even the assembly of multi-domain proteins. These interactions very often lead to the formation of stable protein–protein or protein-ligand complexes that are essential to perform their biological functions.

CONCLUSION: The Protein-Ligand interaction plays a significant role in structural based drug designing. In the present work we have taken the receptor Angiotensin converting enzyme 2 and identified the drugs that were used against SARS. They are Lopinavir, Ribavirin and Ritonavir.When the receptor (ACE-2) was docked with four drugs the energy value obtained is: Lopinavir (-55.81), Ritonavir (-46.95). Further extension of this, We have tried to look for the most probable analog of the respective drugs, which specified earlier.When the modified drugs were docked against the same receptor the energy value obtained was: Lopinavir analog 3 (-59.84), Ritonavir analog 4 (-77.4). From this We can conclude that some of the modified drugs are better than the original drugs.Of these molecules Lopinavir analog 3,Ritonavir analog4 are probable lead molecules than the rest of the drugs for SARS owing to their high-energy value. This infers that the lead molecule is one with maximum interaction having high negative e-value.Thus the concept of protein-Ligand interaction helps in designing new drugs for SARS (Severe Acute Respiratory Syndrome). Further work can be carried out to improve the steric compatibility of the drugs based upon the work done above for a more energy efficient binding of the drug to the receptor

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