A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

Moiani, Davide; Tainer, John A.

doi:10.3389/fmolb.2024.1442267

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

Journal Article · Thu Nov 28 00:00:00 EST 2024 · Frontiers in Molecular Biosciences

DOI:https://doi.org/10.3389/fmolb.2024.1442267· OSTI ID:2497319

Moiani, Davide ^[1]; Tainer, John A. ^[2]

Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center; Moiani Research Inc., Missouri City, TX (United States)
Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center; Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology. Our GL pipeline integrates experimental and predicted structures to efficiently discover leads, allowing early-structure and early-testing (ESET) experiments by many laboratories. By employing an efficient VS protocol to examine protein-protein interfaces (PPIs) and allosteric interactions, we identify ligand binding sites beyond active sites, leveraging in silico advances for molecular docking and modeling to screen PPIs and multiple targets. A diverse 3,174 compound ESET library combines Diamond Light Source DSI-poised, Protein Data Bank fragments, and FDA-approved drugs to span relevant chemotypes and facilitate downstream hit evaluation efficiency for academic laboratories. Two VS per library and multiple ranked ligand binding poses enable target testing for several DDR targets. This GL library and protocol can thus strategically probe multiple DDR network targets and identify readily available compounds for early structural and activity testing to overcome bottlenecks that can limit timely breakthrough drug discoveries. By testing accessible compounds to dissect multi-functional DDRs and suggesting inhibitor mechanisms from initial docking, the GL approach may enable more groups to help accelerate discovery, suggest new sites and compounds for challenging targets including emerging biothreats and advance cancer biology for future precision medicine clinical trials.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: Cancer Prevention and Research Institute of Texas; National Cancer Institute (NCI); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science (BSS)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2497319

Alternate ID(s):: OSTI ID: 2511087

Journal Information:: Frontiers in Molecular Biosciences, Journal Name: Frontiers in Molecular Biosciences Vol. 11; ISSN 2296-889X

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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