9TDQ
Crystal structure of CHIKV nsp3 macrodomain with MDOLL-0273
This is a non-PDB format compatible entry.
Summary for 9TDQ
| Entry DOI | 10.2210/pdb9tdq/pdb |
| Descriptor | Non-structural protein 3, 2-[2-(2,3-dimethylindol-1-yl)-2-oxidanylidene-ethyl]sulfanyl-4-oxidanyl-1H-pyrimidin-6-one (3 entities in total) |
| Functional Keywords | inhibitor, chikv macrodomain, mdoll-0273, viral protein |
| Biological source | Chikungunya virus |
| Total number of polymer chains | 4 |
| Total formula weight | 72374.04 |
| Authors | |
| Primary citation | Duong, M.T.H.,Parviainen, T.A.O.,Thiruvaiyaru, A.,Ahola, T.,Heiskanen, J.P.,Lehtio, L. Discovery of thiobarbiturate-indole scaffold as a selective inhibitor targeting chikungunya virus nsP3 macrodomain through a cryptic binding pocket. Eur.J.Med.Chem., 318:119182-119182, 2026 Cited by PubMed Abstract: Chikungunya virus (CHIKV) outbreaks impose significant burdens on healthcare systems and raise an urgent need for effective antiviral therapies. So far there are no specific drugs against CHIKV infection. CHIKV-encoded macrodomain is critical for virulence and counteracts the host immune response, representing a promising antiviral drug target. Here, we describe small molecule inhibitors targeting the CHIKV macrodomain. Compound 1 (MDOLL-0273) was identified through a high-throughput screening using a fluorescence resonance energy transfer based assay, exhibiting an IC of 8.9 μM, and its inhibitory activity was validated through multiple orthogonal assays. The compound features a thiobarbiturate-indole scaffold and shows high selectivity over a panel of human and viral ADP-ribose binding and hydrolyzing proteins. X-ray crystallography revealed that the inhibitor occupies an adenine binding site of the macrodomain and extends into a novel cryptic pocket. Guided by structure-activity relationship studies, compound 11 (MDOLL-0591) of the developed series with similar IC of 10 μM but with increased lipophilicity was discovered to have antiviral activity against CHIKV in cell culture, demonstrating that macrodomain could be targeted in virus infections. PubMed: 42531898DOI: 10.1016/j.ejmech.2026.119182 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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