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Influenza hemagglutinin is the main protein of the viral membrane playing the crucial role in attaching the virus to a healthy cell for the subsequent fusion of the virus with the host cell membrane which is attractive target for design of effective inhibitors. In a recent study [1] structures of influenza hemagglutinin complexed with commercial antiviral drug umifenovir (Arbidol) were obtained by X-ray diffraction analysis. The model of the umifenovir action as an inhibitor was described based on the analysis of the static structures of the hemagglutinin-umifenovir complexes. As reported, the binding of inhibitor molecules in symmetric sites forms a network of non-covalent interactions that strengthen the high-conserved stem region of hemagglutinin prohibiting subsequent conformational changes necessary for infection. However, umifenovir binding site in new structures is at ~ 16 Å away from the position predicted earlier by mass spectrometry and computer simulation methods [2-3]. Moreover, only one of four single point mutations which cause the resistance to umifenovir is located near both predicted sites whereas for other ones the direct influence is hard to hypothesize without additional analysis. Consequently, it is important to investigate the process of umifenovir binding by hemagglutinin in molecular dynamics with the ability to calculate free energy landscape of the process. In this work we have been developing the strategy of the metadynamics approach to scan all surface of hemagglutinin for umifenovir binding sites to refine the results of experiments. To restore free energy landscape of the process and describe all possible binding modes the so-called collective variables have been implemented: spherical coordinates of radius vector between centers of mass of protein and ligand while keeping the molecule close to protein surface by restraining coordination number. The set of collective variables allowed moving the ligand from one predicted site to another around the protein along with the complete free energy landscape on chosen set of collective variables. We propose that obtained ensemble of umifenovir molecule orientations corresponding the major minima on the landscape might also serve as a starting point for modeling hemagglutinin structural rearrangements during fusion with host’s cell membrane for resolving contradictory results of static X-ray crystallographic structures. The reported study was funded by RFBR according to the research project № 18-315-00390 References: 1. Rameshwar U. Kadam and Ian A. Wilson. Proc. Natl. Acad. Sci. USA. 2017. V. 114(2). PP. 206-214. doi: 10.1073/pnas.1617020114. 2. Leneva IA, Russell RJ, Boriskin YS, Hay AJ. Antiviral Research. 2009. V. 81(2). PP. 132–140. DOI:10.1016/j.antiviral.2008.10.009 3. Nasser ZH, Swaminathan K, Müller P, Downard KM. Antiviral Research. 2013. V. 100(2). PP. 399–406. DOI:10.1016/j.antiviral.2013.08.021