Our Research on COVID 19

INTRODUCTION

COVID-19, a pandemic viral disease, requires immediate attention. Efforts across various fronts are on to identify effective and safe interventions to treat the infection. We at Atrimed Biotech have a well established and validated chemi-informatics platform using which we perform in-silico drug designing, safety and efficacy assessments.

We have applied this platform in two ways to screen for possible COVID-19 interventions.

We are currently screening a collection of over 4000 repurposed drugs to determine their suitability for COVID-19 intervention. Presently, we have performed homology modelling, molecular docking studies and molecular dynamic simulations with these repurposed drugs against 2 SARS-COV-2 target proteins – the Spike (S) protein and the Envelope (E) protein. We continue to work on identifying the suitability of these drugs against 4 more viral target proteins.
We now offer our in silico findings as a free database for interested parties who wish to undertake validation studies for these repurposed drugs.

We have completed an initial screen of our in-house developed secondary metabolite library of over 3.5 lakh molecules for novel antivirals against a set of 6 viral targets. Further in-depth screens are underway.
This is an in-house proprietary project.

THE 6 TARGETS

Let us take a detailed look into the 6 selected viral targets we are currently screening for
(note: all sequences based on Wuhan strain NC_045512.2)

1) SPIKE GLYCOPROTEIN

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

2) ENVELOPE PROTEIN

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

3) IMPORTIN α3

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

4) 3-CHYMOTRYPSIN-LIKE CYSTEINE PROTEASE (3CLPro)

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

5) PAPAIN-LIKE PROTEINASE (PL-PRO)

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

6) RNA-DEPENDANT RNA POLYMERASE (RdRp)

There are 4 subunits of the Spike (S) protein. The Spike protein S1 subunit attaches the virion to the cell membrane by interacting with host receptor human ACE2 and CLEC4M/DC-SIGNR, initiating the infection. Spike protein S2 subunit mediates the fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2′ subunit acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon viral endocytosis. Finally, the Spike protein subunit S3 houses the RBD (receptor binding domain). We have targeted this subunit S3 in our screening studies.

THE RATIONALE BEHIND REPURPOSING AND OUR APPROACH

Human coronavirus 2019-nCoV (also known as SARS-CoV-2) is causing a pandemic with significant morbidity and mortality making it imperative for effective interventions with increasing urgency. With time being short and no effective novel drugs targeting SARS-CoV-2 available as yet, drug repurposing of existing drugs is emerging as the most efficient discovery based intervention strategy. The strategy can be beneficial because of its shortened discovery time, reduced cost and already clinically proven safety for human use. With these advantages in mind, we have performed an in silico drug repurposing study implementing successful concepts of computer aided drug design (CADD) technology against the first 2 SARS-COV-2 target proteins – the Spike (S) protein and the Envelope (E) protein.
We continue to work on identifying the suitability of these drugs against the remaining 4 viral target proteins described above.

Below is a representation of our approach/research model for the repurposing studies –

THE DELIVERABLE UPON QUERY –
Here we present a sample deliverable.

LINK TO LIST OF REPURPOSED DRUGS AND RELATED INFORMATION
Please find the list of drugs, target viral proteins and other information at the link below –

THE PLANT BASED SMALL
MOLECULE PROJECT

We follow the same approach for our in-house plant based small molecule screening studies for novel antivirals. We have created a small molecule library of over 450,000 plant secondary metabolites. This library has now been screened for molecules with anti-SARS-CoV-2 activity.
First, We performed sequence analysis of the complete genome of SARS_nCoV-2 and identified 6 viral protein targets. These have been described in detail above.
We then performed homology modelling of the viral target protein structures to prepare them for docking studies with our in-house developed phyto-molecule library. Then, molecular docking was performed using Glide application in two stages with three levels of precision to generate highly accurate in silico HITS/LEADS. Our library of close to 5 lakh molecules has been whittled down based on their chemical nature and predicted safety in humans, to generate a list of molecules that we now intend to investigate further in in vitro and in vivo validation studies against the SARS-CoV-2 virus to confirm the safety and therapeutic efficacy of the molecules.
Encouragingly, since the molecules are present in plants, which have been safely used regularly in Ayurveda, the anti-viral activity of the plants can be rapidly established. Once safety is established, we can also formulate and commercialise the oral antiviral quickly.

CONTACT –
Please contact us at covid@atrimed.com for further details and queries

SAMPLE QUERY REPORT

SAMPLE QUERY LIGAND -XXX

QUERY TARGET – SPIKE GLYCOPROTEIN

INTRODUCTION TO TARGET
(SPIKE GLYCOPROTEIN)

The entry of SARS-CoV-2 into host cells is mediated by homotrimer, protruding and transmembrane SARS-CoV-2 S glycoprotein localised on viral surface. The total SARS-CoV-2 S is comprised of two functional subunits individually responsible for interaction with host cell receptor (S1 subunit) and fusion of the viral and cellular membranes (S2 subunit).
Corona virus (CoVs), SARS-CoV-2 S is cleaved at the boundary between the S1 and S2 subunits, which remain non-covalently bound in the perfusion conformation. The receptor-binding domain (RBD) site on distal S1 subunit contributes to the stabilisation of the profusion state of the membrane-anchored S2 subunit that contains the fusion machinery.
For all CoVs, spike glycoprotein is further cleaved by host proteases at the so-called S20 site located immediately upstream of the fusion peptide.
This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes. As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor binding and proteolytic processing of the SARS-CoV-2 S protein to promote the fusion of SARS-CoV-2 cells.

Physicochemical parameters of Ligand
Molecular Weight –
Hydrogen Bond Donor Count –
Hydrogen Bond Acceptor Count –
Rotatable Bond Count –
XLogP3-AA –

MOLECULAR DOCKING INFORMATION

A

B

Figure 1: A: Two dimensional (2D) illustration of Ligand interaction in the ACE2 binding site on RBD of SARS-CoV-2 S facilitated by 5 H-Bonds shown in pink arrow. B: Three dimensional (3D) illustration of Ligand interaction in the ACE2 binding site on RBD of SARS-CoV-2 S facilitated by 5 H-Bonds shown in yellow dotted line.

Company Updates

Atrimed Pharmaceuticals is a 15-year-old company located in Bangalore, India. We are growing rapidly with a sales network backed by effective products and strong R&D.

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