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One potential strategy is synthesizing or identifying small compounds that can specifically target the active site of an essential enzyme and prevent virus replication. Previous site\u2010directed mutagenesis studies have demonstrated the crucial role of the macrodomain, which is a part of non\u2010structural protein 3 (nsP3), in virus replication. Exploiting this fact, the macrodomain can be targeted to discover a natural substance that can inhibit its function and thereby impede virus replication. With this aim, the present study focused on potential CHIKV nsP3 macrodomain (nsP3<jats:sup>MD<\/jats:sup>) inhibitors through <jats:italic>in\u2009silico<\/jats:italic>, <jats:italic>in\u2009vitro<\/jats:italic> and cell\u2010based methods. Through virtual screening of the natural compound library, nine nsP3<jats:sup>MD<\/jats:sup> inhibitors were initially identified. Molecular dynamics (MD) simulations were employed to evaluate these nine compounds based on the stability of their ligand\u2013receptor complexes and energy parameters. Target analysis and ADMET (i.e. absorption, distribution, metabolism, excretion and toxicity) prediction of the selected compounds revealed their drug\u2010like characteristics. Subsequent <jats:italic>in\u2009vitro<\/jats:italic> investigation allowed us to narrow the selection down to one compound, <jats:italic>N<\/jats:italic>\u2010[2\u2010(5\u2010methoxy\u20101H\u2010indol\u20103\u2010yl) ethyl]\u20102\u2010oxo\u20101,2\u2010dihydroquinoline\u20104\u2010carboxamide, which exhibited potent inhibition of CHIKV growth. This molecule effectively inhibited CHIKV replication in the stable embryonal rhabdomyosarcoma cell line capable of producing CHIKV. Our findings demonstrate that the selected compound possesses substantial anti\u2010CHIKV nsP3<jats:sup>MD<\/jats:sup> activity both <jats:italic>in\u2009vitro<\/jats:italic> and <jats:italic>in\u2009vivo<\/jats:italic>. This work provides a promising molecule for further preclinical studies to develop a potential drug against the CHIKV.<\/jats:p>","DOI":"10.1111\/febs.17066","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T05:41:01Z","timestamp":1706852461000},"page":"2656-2673","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<i>In silico<\/i> identification of chikungunya virus replication inhibitor validated using biochemical and cell\u2010based approaches"],"prefix":"10.1111","volume":"291","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-4633","authenticated-orcid":false,"given":"Meenakshi","family":"Chaudhary","sequence":"first","affiliation":[{"name":"Virology Laboratory, Department of Life Sciences Shiv Nadar Institute of Eminence  Greater Noida 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