Unraveling receptors used by SARS-CoV-2 for entry and the exact positively selected sites on the Spike (S) protein associated with this process can provide insights into the viral transmission and reveal therapeutic targets. Except for ACE2, accumulating evidence indicates that the S protein potentially recognizes other receptors like CD147. Therefore, methods for new receptors identification are urgently needed. To account for this, the following three aspects will be explored in this proposal. First, with increasing genome sequence data to investigate evolution and selection patterns and to assess their influence on the structure and function of the S protein. Second, integrating data from multiple sources design and realize new receptor prediction framework, and in combination with results from the first step filtering out most potential receptors for experiment verification.