The size matters? A computational tool to design bivalent ligands

Pérez‐Benito, Laura; Henry, Alasdair L.; Matsoukas, Minos‐Timotheos; López, L. Madero; Pulido, Daniel; Royo, Míriam; Cordomí, Arnau; Tresadern, Gary; Pardo, Leonardo

doi:10.1093/bioinformatics/bty422

Cited by 32 publications

(42 citation statements)

References 49 publications

(68 reference statements)

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“…This specificity is likely to be lost with the trimeric agent 21 , where the potency is in double digit micromolar region as well. Our data are similar to what has been seen in investigations of linker lengths in dimeric agents targeting G protein-coupled receptors [ 39 ], estrogen receptors [ 40 ], proteolysis targeting chimeras [ 39 ], among others [ 41 ].…”

Section: Resultssupporting

confidence: 89%

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

Maslivetc

Laguera

Chandra

et al. 2021

IJMS

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In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,β- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar antiproliferative potencies in cancer cells. In the current work, we synthesized dimeric and trimeric variants of such compounds in an effort to discover compounds that could crosslink biological primary amine containing targets. We showed that such compounds retain the pyrrolylation ability and possess enhanced single-digit micromolar potencies toward apoptosis-resistant cancer cells. Target identification studies of these interesting compounds are underway.

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Section: Resultssupporting

confidence: 89%

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

Maslivetc

Laguera

Chandra

et al. 2021

IJMS

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“… 28 − 30 Furthermore, more recent in silico methods can also guide the prioritization of degraders as well as linker design that benefit from increased protein surface complementarity to reduce the time for exploring structure–activity relationships (SARs). 24 , 31 − 33 Combining experimental and modeling approaches to prioritize stable ternary complexes has been productive 11 but may also bias discovery of degraders toward molecules that primarily access static and long-lived populations. Thus, opportunities where sufficiently fast protein degradation occurs, such that a small fraction of ternary complex is present, could go unrecognized.…”

Section: Induced Cooperativity and Pursuit Of Privileged Ternary Complexes For Proteasomal Degradationmentioning

confidence: 99%

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Rodriguez‐Rivera

Levi

2021

ACS Cent. Sci.

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Diverging from traditional target inhibition, proteasomal protein degradation approaches have emerged as novel therapeutic modalities that embody distinct pharmacological profiles and can access previously undrugged targets. Small molecule degraders have the potential to catalytically destroy target proteins at substoichiometric concentrations, thus lowering administered doses and extending pharmacological effects. With this mechanistic premise, research efforts have advanced the development of small molecule degraders that benefit from stable and increased affinity ternary complexes. However, a holistic framework that evaluates different degradation modes from a catalytic perspective, including focusing on kinetically favored degradation mechanisms, is lacking. In this Outlook, we introduce the concept of an induced cooperativity spectrum as a unifying framework to mechanistically understand catalytic degradation profiles. This framework is bolstered by key examples of published molecular degraders extending from molecular glues to bivalent degraders. Critically, we discuss remaining challenges and future opportunities in drug discovery to rationally design and phenotypically screen for efficient degraders.

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“…A similar approach has already been shown to be effective in designing bivalent linkers for various model systems, including a PROTAC-mediated ternary complex. 59 Generally, linkers that are too long to bridge between the two pockets in a given protein-protein docked pose will coil upon themselves, whereas linkers that are too short must stretch their bonds to accomplish the bridging. These contrasting behaviors can thus conceptually be used to identify protein-protein poses that can suitably be bridged by a given PROTAC linker, resulting in a goodness-of-fit or compatibility metric between a PROTAC's linker and a given E3 ligase/target with the default MOE AMBER10:EHT forcefield.…”

Section: Validation Of Methods 4bmentioning

confidence: 99%

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies

Drummond¹,

Henry²,

Li³

et al. 2020

Preprint

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Extending upon our previous publication (Drummond and Williams, J. Chem. Inf. Model.2019, 59, 1634), in this work two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different possible PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.

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The size matters? A computational tool to design bivalent ligands

Cited by 32 publications

References 49 publications

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via NewIn SilicoMethodologies

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