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An efficient chemical screening method for structure-based inhibitors to nucleic acid enzymes targeting the DNA repair-replication interface and SARS CoV-2

  • Moiani, Davide1, 2
  • Link, Todd M.1, 2
  • Brosey, Chris A.1, 2
  • Katsonis, Panagiotis3
  • Lichtarge, Olivier3
  • Kim, Youngchang4, 5
  • Joachimiak, Andrzej4, 5
  • Ma, Zhijun6
  • Kim, In-Kwon6
  • Ahmed, Zamal1, 2
  • Jones, Darin E.7
  • Tsutakawa, Susan E.8
  • Tainer, John A.1, 2, 8
  • 1 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
  • 2 Department of Molecular & Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
  • 4 Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, United States
  • 5 Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, United States
  • 6 Department of Chemistry, University of Cincinnati, Cincinnati, OH, United States
  • 7 Department of Pharmaceutical Sciences, The University of Arkansas for Medical Sciences, Little Rock, AR, United States
  • 8 Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
Published Article
Methods in Enzymology
Elsevier Inc.
Publication Date
Sep 27, 2021
DOI: 10.1016/bs.mie.2021.09.003
PMCID: PMC8474023
PubMed Central
  • Article


We present a Chemistry and Structure Screen Integrated Efficiently (CASSIE) approach (named for Greek prophet Cassandra) to design inhibitors for cancer biology and pathogenesis. CASSIE provides an effective path to target master keys to control the repair-replication interface for cancer cells and SARS CoV-2 pathogenesis as exemplified here by specific targeting of Poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose glycohydrolase ARH3 macrodomains plus SARS CoV-2 nonstructural protein 3 (Nsp3) Macrodomain 1 (Mac1) and Nsp15 nuclease. As opposed to the classical massive effort employing libraries with large numbers of compounds against single proteins, we make inhibitor design for multiple targets efficient. Our compact, chemically diverse, 5000 compound Goldilocks (GL) library has an intermediate number of compounds sized between fragments and drugs with predicted favorable ADME (absorption, distribution, metabolism, and excretion) and toxicological profiles. Amalgamating our core GL library with an approved drug (AD) library, we employ a combined GLAD library virtual screen, enabling an effective and efficient design cycle of ranked computer docking, top hit biophysical and cell validations, and defined bound structures using human proteins or their avatars. As new drug design is increasingly pathway directed as well as molecular and mechanism based, our CASSIE approach facilitates testing multiple related targets by efficiently turning a set of interacting drug discovery problems into a tractable medicinal chemistry engineering problem of optimizing affinity and ADME properties based upon early co-crystal structures. Optimization efforts are made efficient by a computationally-focused iterative chemistry and structure screen. Thus, we herein describe and apply CASSIE to define prototypic, specific inhibitors for PARG vs distinct inhibitors for the related macrodomains of ARH3 and SARS CoV-2 Nsp3 plus the SARS CoV-2 Nsp15 RNA nuclease.

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