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Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
In silico analysis of the Chikungunya virus and SARS-CoV-2 Macrodomain
Vikas Tiwari1, Moira Rachman1, Kenneth Huang1
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Abstract:
The macrodomain of the Chikungunya virus NSP3 protein (ChikV Mac1) hydrolyzes mono-ADP ribose post-translational modifications on the human host proteins. Mutations in Mac1 reduce ChikV virulence. Thus, ChikV Mac1 is a viral drug target. While no potent ChikV Mac1 inhibitors are available, high-affinity inhibitors were developed for Mac1 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we rationalize this difference in the ligand binding affinity in terms of three differences in the binding site structure and dynamics. First, the apo ChikV Mac1 binding site exhibits substantially more conformational heterogeneity than that of SARS-CoV-2, based on microsecond-scale molecular dynamics simulations; it also has a less druggable binding site, based on program SiteMap. Second, water binding sites overlapping with the ligand binding site in ChikV Mac1 are predicted by program WaterMap to have a stronger affinity for water molecules than the corresponding sites in SARS-CoV-2 Mac1, thus decreasing ligand binding affinity. Finally, a smaller number of Mac1 residues interacts persistently with ADP-ribose in holo ChikV Mac1 than in SARS-CoV-2. With these rationalizations in hand, we designed ligands of ChikV Mac1 using a fragment growth strategy; subsequent molecular dynamics simulations of a representative ligand in complex with ChikV Mac1 substantiated our design.
Insights
Chikungunya virus NSP3 protein (ChikV Mac1) targets host proteins. Differences in binding sites explain why ChikV Mac1 has fewer inhibitors than SARS-CoV-2 Mac1, guiding new drug design.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- The Chikungunya virus NSP3 protein's macrodomain (ChikV Mac1) modifies host proteins via mono-ADP ribose, and mutations affecting this reduce viral virulence, making ChikV Mac1 a potential drug target.
- Despite ChikV Mac1 being a viral drug target, potent inhibitors are lacking, unlike for the structurally similar Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Mac1.
Purpose of the Study:
- To rationalize the differences in ligand binding affinity between ChikV Mac1 and SARS-CoV-2 Mac1.
- To identify structural and dynamic factors contributing to the lower druggability of ChikV Mac1.
- To design novel ChikV Mac1 ligands based on rationalized binding site characteristics.
Main Methods:
- Microsecond-scale molecular dynamics simulations to assess binding site conformational heterogeneity.
- Computational analysis using SiteMap and WaterMap to evaluate binding site druggability and water molecule affinity.
- Analysis of protein-ligand interactions in holo ChikV Mac1 compared to SARS-CoV-2 Mac1.
- Fragment-based ligand design and molecular dynamics simulations for validation.
Main Results:
- ChikV Mac1 exhibits greater apo binding site conformational heterogeneity and lower druggability compared to SARS-CoV-2 Mac1.
- Water molecules bind with higher affinity in ChikV Mac1's ligand-binding site, reducing ligand affinity.
- Fewer Mac1 residues persistently interact with ADP-ribose in the Chikungunya virus compared to SARS-CoV-2.
- Designed ligands demonstrated potential for ChikV Mac1 inhibition, validated by molecular dynamics.
Conclusions:
- Differences in binding site dynamics, water occupancy, and residue interactions explain the lower ligand affinity for ChikV Mac1 compared to SARS-CoV-2 Mac1.
- The study provides a rational basis for designing potent ChikV Mac1 inhibitors.
- The developed fragment-growth strategy and validated ligands offer a promising starting point for Chikungunya virus therapeutics.
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