{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:02:03Z","timestamp":1787828523512,"version":"build-2784847793"},"reference-count":104,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R35-GM144042"],"award-info":[{"award-number":["R35-GM144042"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01-AI139216"],"award-info":[{"award-number":["R01-AI139216"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a framework for analyzing de novo peptides\u2014evaluation along a replication\/restitution axis\u2014and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead inhibitors. We also provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.<\/jats:p>","DOI":"10.1093\/protein\/gzae007","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T10:14:39Z","timestamp":1715940879000},"source":"Crossref","is-referenced-by-count":9,"title":["DexDesign: an OSPREY-based algorithm for designing <i>de novo<\/i> D-peptide inhibitors"],"prefix":"10.1093","volume":"37","author":[{"given":"Nathan","family":"Guerin","sequence":"first","affiliation":[{"name":"Department of Computer Science, Duke University , 308 Research Drive, Durham, NC 27708 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Childs","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University , 124 Science Drive, Durham, NC 27708 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine , 307 Research Drive, Durham, NC 22710 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6884-4398","authenticated-orcid":false,"given":"Bruce R","family":"Donald","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Duke University , 308 Research Drive, Durham, NC 27708 , United States"},{"name":"Department of Chemistry, Duke University , 124 Science Drive, Durham, NC 27708 , United States"},{"name":"Department of Biochemistry, Duke University School of Medicine , 307 Research Drive, Durham, NC 22710 , United States"},{"name":"Department of Mathematics, Duke University , 120 Science Drive, Durham, NC 27708 , United 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