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

Davide Moiani, Todd M. Link, Chris A. Brosey, Panagiotis Katsonis, Olivier Lichtarge, Youngchang Kim, Andrzej Joachimiak, Zhijun Ma, In Kwon Kim, Zamal Ahmed, Darin E. Jones, Susan E. Tsutakawa, John A. Tainer

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Title of host publicationThe DNA Replication-Repair Interface
EditorsBrandt F. Eichman
PublisherAcademic Press Inc.
Pages407-431
Number of pages25
ISBN (Print)9780323907330
DOIs
StatePublished - Jan 2021

Publication series

NameMethods in Enzymology
Volume661
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988

Keywords

  • Cancer
  • Chemical library
  • DNA replication and repair
  • Drug discovery
  • Sars-COV2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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