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It has demonstrated effectiveness in treating many complex diseases , but it has a higher risk of adverse drug reactions. Hence, the prediction of polypharmacy side effects is an essential step in drug testing, especially for new drugs. This paper shows that the current knowledge graph (KG) based state-of-the-art approach to polypharmacy side effect prediction does not work well for new drugs, as they have a low number of known connections in the KG. We propose a new method , SimVec, that solves this problem by enhancing the KG structure with a structure-aware node initialization and weighted drug similarity edges. We also devise a new 3-step learning process, which iteratively updates node embeddings related to side effects edges, similarity edges, and drugs with limited knowledge. Our model significantly outperforms existing KG-based models. Additionally, we examine the problem of negative relations generation and show that the cache-based approach works best for polypharmacy tasks.<\/jats:p>","DOI":"10.1186\/s13321-022-00632-5","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T13:48:54Z","timestamp":1658929734000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SimVec: predicting polypharmacy side effects for new drugs"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"http:\/\/orcid.org\/0000-0002-3481-0840","authenticated-orcid":false,"given":"Nina","family":"Lukashina","sequence":"first","affiliation":[]},{"given":"Elena","family":"Kartysheva","sequence":"additional","affiliation":[]},{"given":"Ola","family":"Spjuth","sequence":"additional","affiliation":[]},{"given":"Elizaveta","family":"Virko","sequence":"additional","affiliation":[]},{"given":"Aleksei","family":"Shpilman","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,7,26]]},"reference":[{"key":"632_CR1","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1126\/scitranslmed.3003377","volume":"4","author":"N Tatonetti","year":"2012","unstructured":"Tatonetti N, Ye P, Daneshjou R, Altman R (2012) Data-driven prediction of drug effects and interactions. 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