What is Known - StructuralGenomicsConsortium/CNP25-CHIKV-nsP3-Macrodomain GitHub Wiki

The CHIKV biology is still not fully understood, in particular the functions of the non-structural protein 3 (nsP3). The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence, but no small molecule drug targeting CHIKV nsP3 has been identified yet. The first study to report fragment hits that have potential binding to nsP3MD discovered by virtually screening a fragment library and X-ray crystallography was performed by Zhang et al in Jan 2021 1.

These fragments have a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Another core scaffold shared by other fragments hits was 2-oxo-5,6-benzopyrimidine-4-carboxylic acid which exhibited anti-CHIKV activity with an IC50 of 23 μM. The fragment-based drug discovery approach is essential to develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on fragments as a starting point, starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The starting point for the Zhang et al was the 2-pyrimidone-4-carboxylic acid scaffold in which In silico studies suggested as an important core that could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential pan-antiviral activity [1].

Here are the The co-crystal structure of CHIKV nsP3MD with ADP-ribose and The co-crystal structure of CHIKV nsP3MD with SRI-40582 respectively 1:

All fragments that formed co-crystal structures with nsP3MD are shown as following 1::

Exploring fragment growth based on the pyrimidone carboxylic acid scaffold 1:

The structure of CHIKV nsP3MD-SRI-43750 and the docking results of SRI-43750 bound to macrodomains from VEEV, SARS, MERS and SARS-CoV-2 is here 1:

a) Co-crystal structure of CHIKV nsPMD-SRI-43750 (PDB ID: 6W8M). b) Docking model of SRI-43750 in the macrodomain of VEEV (PDB ID: 3GQO) 2. c) Docking result of SRI-43750 in the macrodomain of SARS (PDB ID: 2FAV) 3. d) Docking model of SRI-43750 in the macrodomain of MERS (PDB ID: 5HOL) 4. e) Docking model of SRI-43750 in the macrodomain of SARS-CoV-2 (PDB ID: 6W02) 3. The conserved residues interacting with SRI-43750 in the macrodomain structures of alphaviruses and coronaviruses are highlighted in yellow sticks and SRI-43750 shown in cyan sticks in all structures. Hydrogen bonds, hydrophobic contacts, and π-π stacking are indicated by cyan, orange, and dark green dashed lines respectively.