title: DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites.
abstract: Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by "traditional" drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket "observed" from within the protein to the topography "observed" when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human antiapoptotic protein Mcl-1 and found that four of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 μM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions.
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Ragul
authors.initials: R
authors.lastname: Gowthaman
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Sven A
authors.initials: SA
authors.lastname: Miller
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Jittasak
authors.initials: J
authors.lastname: Khowsathit
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Lan
authors.initials: L
authors.lastname: Lan
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: David K
authors.initials: DK
authors.lastname: Johnson
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Asokan
authors.initials: A
authors.lastname: Anbanandam
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Roy
authors.affiliation: Center for Computational Biology, ‡Department of Molecular Biosciences, §Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, ∥Department of Radiation Oncology, ⊥Biomolecular NMR Laboratory, #Department of Medicinal Chemistry, and ∇High Throughput Screening Laboratory University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66045-7534, United States.
authors.forename: John
authors.initials: J
authors.lastname: Karanicolas
mesh_terms: D006801:Humans; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013499:Surface Properties
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein