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The genus Orthoflavivirus includes enveloped viruses transmitted by ticks and mosquitoes. These viruses cause dangerous diseases such as dengue fever, Zika fever, West Nile fever, and tick-borne encephalitis. By 2024, there are no approved direct-acting antiviral drugs against orthoflavivirus infections. Vaccines have been developed to prevent diseases caused by some orthoflaviviruses, but they cannot be used to treat diseases after onset, do not provide complete protection against viral infection, and their development and widespread use are complicated by antibody-dependent enhancement of infection, which is observed for some flaviviruses (dengue virus, Zika virus). Non-structural protein NS1 plays an important role in the reproduction cycle of orthoflaviviruses by stabilising the replicative complex. Moreover, in the acute form of the disease it causes hyperpermeability of blood vessels due to interaction with endothelial cells and destruction of the glycocalyx. Small molecules that interact with the NS1 protein may be used as lead compounds for the discovery of anti-orthoflavivirus drugs. However, complexes of the orthoflavivirus NS1 protein with small molecules have not been described, complicating the application of structure-based molecule design. Nevertheless, the structure of the apo form of the NS1 protein from mosquito-borne orthoflaviviruses was studied using X-ray crystallography and cryo-electron microscopy, resulting in seven full-length structures. These structures can be used as templates for homology modelling for other orthoflavivirus NS1 proteins, thus producing enough structural data to employ ensemble docking. Recently we described a method of systematic ensemble docking [1], which uses all available structural data for docking-based virtual screening of small molecules. Though the improvement in accuracy due to the usage of multiple structures of the same protein has been shown multiple times, the question whether using homologous proteins from organisms of different species may help to find potential broad-spectrum inhibitors remains open. We have performed homology modelling based on the sequences of epidemiologically significant orthoflaviviruses. Since there are no available crystal structures of NS1 proteins from tick-borne orthoflaviviruses, the available structures deriving from mosquito-borne orthoflaviviruses were used, though the amino acid sequences of these groups have inter-group similarity between 34 and 41 percent. The systematic selection process by the diversity of the atomic coordinates was perplexed by the randomness of coordinate generation in the flexible parts of NS1 protein structure. That is why we decided to determine whether the ensemble could be selected based on docking results. The models and experimentally determined structures were used for docking of 5000 diverse drug-like molecules from ZINC15. The results were ranked and the sum of ranks distributions and rank-order correlation were analysed to check discrimination ability between virtual screening results and randomly generated data. Nevertheless, the applicability of homology modelling of diverse closely related proteins as the structures source for ensemble docking remains limited.