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4 results on '"Donald, Bruce R."'

1. DexDesign: A New OSPREY-Based Algorithm for Designing de novo D-peptide Inhibitors

Author

Guerin, Nathan, Childs, Henry, Zhou, Pei, Donald, Bruce R., Goos, Gerhard, Series Editor, Hartmanis, Juris, Founding Editor, van Leeuwen, Jan, Series Editor, Hutchison, David, Editorial Board Member, Kanade, Takeo, Editorial Board Member, Kittler, Josef, Editorial Board Member, Kleinberg, Jon M., Editorial Board Member, Kobsa, Alfred, Series Editor, Mattern, Friedemann, Editorial Board Member, Mitchell, John C., Editorial Board Member, Naor, Moni, Editorial Board Member, Nierstrasz, Oscar, Series Editor, Pandu Rangan, C., Editorial Board Member, Sudan, Madhu, Series Editor, Terzopoulos, Demetri, Editorial Board Member, Tygar, Doug, Editorial Board Member, Weikum, Gerhard, Series Editor, Vardi, Moshe Y, Series Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, and Ma, Jian, editor

Published
2024
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3. DexDesign: A new OSPREY-based algorithm for designing de novo D-peptide inhibitors.

Author

Guerin N, Childs H, Zhou P, and Donald BR

Abstract

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, which enable exponential reductions in the size of the peptide sequence search space. 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 new framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and 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 therapeutic candidates. We provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.

Published
2024
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4. DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.

Author

Guerin N, Childs H, Zhou P, and Donald BR

Subjects
Humans, Drug Design, PDZ Domains, Algorithms, Peptides chemistry, Peptides pharmacology
Abstract

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-evaluation along a replication/restitution axis-and 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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Published
2024
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