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Modelling of ZIKA proteases

Disclaimer: This blog is made public in order to inspire a new generation of enthusiastic people to start working on this neglected disease as soon as possible.

I was doing some side-project especially with flaviviruses and the drug discovery targeting flavivirus proteases. That’s why ZIKA break into the scene of my research as ZIKA is likely to be the next big target in the field of drug discovery and development.

Due its similarity with dengue and hepatitis C the drug hunters have some obvious target in their mind which are targeting NS2B-NS3 and NS5 non-structural proteases. Keeping that in mind I designed two protein structures using homology modeling by Swiss-Model server.

  1. Model of NS5: The sequence of ZIKA NS5 (RNA dependent RNA polymerase) was retrieved from NCBI curated database for ZIKA (Accession Id: YP_009227205.1 and link: http://www.ncbi.nlm.nih.gov/protein/985757036?report=fasta ) and submitted into the Swiss-Model server. The homology modeled structure for ZIKA NS5 was described in Figure 1. The homology model was generated using the crystal structure of Of the full-length Japanese Encephalitis Virus Ns5 (PDB: 4K6M)which has a 69.79% sequence identity and 98% query coverage in the blast run.zika_ns5

Figure 1. 3D homology modeled structure of ZIKA NS5 protease using the template of PDB: 4K6M. The nucleotide was introduced in the binding site to map the binding site residues.

The ligand interaction map (Figure 2) of ZIKA NS5 highlighted plausible binding site residues present in the active site of RNA dependent RNA polymerase.

zika_ns5_liginteraction

Figure 2. Ligand interaction map ZIKA NS5 active site residues with nucleoside.

The quality assessments for the NS5 structure is presented below (Figure 3)

torsion

qmeanns5

local_quality_estimate

Figure 3. Several quality assessment parameter for the homology modeled ZIKA NS5 structure.

The assessment of the structure resulted led me to believe that the modeled structure is well predicted.

2. Model of NS2B-NS3 protease: The model of ZIKA NS2B-NS3 pro was designed using the template of ligand bound structure of Dengue NS2B-NS3 (PDB: 3U1I). A 3D ribbon representation of ZIKA NS2B-NS3 pro is presented in Figure 4.

zika_ns3

Figure 4. The 3D ribbon representation of ZIKA NS2B-NS3 pro using the template structure of Dengue serine protease (PDB: 3 U1I).

Here is the sequence of ZIKA NS2B-NS3 pro:

VDMYIERAGDITWEKDAEVTGNSPRLDVALDESGDFSLVEDDGSGSGVKTGKRSGALWDVPAPKEVKKGETTDGVYRVMTRRLLGSTQV

GVGVMQEGVFHTMWHVTKGSALRSGEGRLDPYWGDVKQDLVSYCGPWKLDAAWDGHSEVQLLAVPPGERARNIQTLPGIFKTKDGDIGAVALDYPAGTSG

SPILDKCGRVIGLYGNGVVIKNGSYVSAITQGRREEET

I ran a 27ns NVT MD simulation to refine the structural model and then uploaded the structure in the MolProbity geometry analysis. The analysis report is mentioned with the attached PDF link prot27000_1-rama

These are just the very basic work but it gives an idea about the binding site which is clearly defined in case of both NS3 and NS5. I realized that there might be a bit more computational study necessary to refine the homology modeled structure but keeping in mind the defined active site, I believe it will be a great starting point for virtual screening and pharamacophore based drug design campaign.

Note: If you are using any of this material for your science or inspired by this short piece of work please cite it accordingly. Happy drug hunting!!


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