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One class of these drugs are non\u2010nucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral reverse transcriptase (RT). First generation NNRTIs were troubled with poor pharmacological properties and drug resistance, incentivizing the development of improved compounds. One class of developed compounds are the 2\u2010naphthyl phenyl ethers, showing promising efficacy against the Y181C RT mutation. Further biochemical and structural work demonstrated differences in potency against the Y181C mutation and binding mode of the compounds. This work aims to understand the relationship between the binding mode and ability to overcome drug resistance using macromolecular x\u2010ray crystallography. Comparison of 2\u2010naphthyl phenyl ethers bound to Y181C RT reveal that compounds that interact with the invariant W229 are more capable of retaining efficacy against the resistance mutation. 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Ultimately, we highlight important considerations for the development of future HIV\u20101 drugs that are able to combat drug resistance.<\/jats:p>","DOI":"10.1002\/pro.3910","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T06:36:25Z","timestamp":1594276585000},"page":"1902-1910","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structural investigation of <scp>2\u2010naphthyl<\/scp> phenyl ether inhibitors bound to <scp>WT<\/scp> and <scp>Y181C<\/scp> reverse transcriptase highlights key features of the <scp>NNRTI<\/scp> binding site"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5662-9375","authenticated-orcid":false,"given":"Vincent N.","family":"Duong","sequence":"first","affiliation":[{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut 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