CROSS: An Efficient Workflow for Reaction-Driven Rescaffolding and Side-Chain Optimization Using Robust Chemical Reactions and Available Reagents

Evers, Andreas; Heßler, Gerhard; Wang, Li-hsing; Werrel, Simon; Monecke, Peter; Matter, Hans

doi:10.1021/jm400404v

Cited by 8 publications

(4 citation statements)

References 59 publications

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“…Evers et al from the Sanofi‐Aventis company reported the CROSS method for either rescaffolding or the optimization of compounds using explicit handling of organic reactions . The CROSS approach relies on the BROOD software to quickly identify pre‐processed fragments that could replace an undesirable core by using “exit vectors” and 3D‐shape analysis .…”

Section: Alternative Approaches For In Silico H2l Optimizationmentioning

confidence: 99%

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

Hoffer

Muller

Roché

et al. 2018

Molecular Informatics

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For several decades, hit identification for drug discovery has been facilitated by developments in both fragment-based and high-throughput screening technologies. However, a major bottleneck in drug discovery projects continues to be the optimization of primary hits from screening campaigns in order to derive lead compounds. Computational chemistry or molecular modeling can play an important role during this hit-to-lead (H2L) stage by both suggesting putative optimizations and decreasing the number of compounds to be experimentally synthesized and evaluated. However, it is also crucial to consider the feasibility of organically synthesizing these virtually designed compounds. Furthermore, the generated molecules should have reasonable physicochemical properties and be medicinally relevant. This review focuses on chemistry-driven and structure-based computational methods that can be used to tackle the difficult problem of H2L optimization, with emphasis being placed on the strategy developed in our laboratory.

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Section: Alternative Approaches For In Silico H2l Optimizationmentioning

confidence: 99%

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

Hoffer

Muller

Roché

et al. 2018

Molecular Informatics

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“…In this collection, 58 medicinal chemistry-relevant chemical reactions commonly used during the H2L optimization stage in the pharmaceutical industry have been encoded in the machine-readable SMARTS format. These reactions have been implemented in several approaches including DOGS ( 25 ), CROSS ( 26 ), PINGUI/SCUBIDOO ( 27 , 28 ), AutoCouple ( 29 ), NAOMINEXT ( 30 ), CHIPMUNK ( 31 ), SwissDrugDesign ( 32 ), AutoGrow4 ( 33 ), OpenChemLib ( 34 ) and eXplore ( 35 ). We also implemented this collection of reactions into our integrated drug design strategy called diversity-oriented target-focused synthesis (DOTS, ( 36 )).…”

Section: Introductionmentioning

confidence: 99%

ChemoDOTS: a web server to design chemistry-driven focused libraries

Hoffer,

Charifi-Hoareau,

Barelier

et al. 2024

Nucleic Acids Research

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In drug discovery, the successful optimization of an initial hit compound into a lead molecule requires multiple cycles of chemical modification. Consequently, there is a need to efficiently generate synthesizable chemical libraries to navigate the chemical space surrounding the primary hit. To address this need, we introduce ChemoDOTS, an easy-to-use web server for hit-to-lead chemical optimization freely available at https://chemodots.marseille.inserm.fr/. With this tool, users enter an activated form of the initial hit molecule then choose from automatically detected reactive functions. The server proposes compatible chemical transformations via an ensemble of encoded chemical reactions widely used in the pharmaceutical industry during hit-to-lead optimization. After selection of the desired reactions, all compatible chemical building blocks are automatically coupled to the initial hit to generate a raw chemical library. Post-processing filters can be applied to extract a subset of compounds with specific physicochemical properties. Finally, explicit stereoisomers and tautomers are computed, and a 3D conformer is generated for each molecule. The resulting virtual library is compatible with most docking software for virtual screening campaigns. ChemoDOTS rapidly generates synthetically feasible, hit-focused, large, diverse chemical libraries with finely-tuned physicochemical properties via a user-friendly interface providing a powerful resource for researchers engaged in hit-to-lead optimization.

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“…To alleviate this problem, several research groups have proposed the use of chemical reaction protocols to guide virtual compound synthesis. Consequently, in recent years, collections of reactions and reactions types have been systematically mined from the chemical literature and, attempts to classify them into reaction types and organize them have been reported. − Research efforts to exploit such reaction sets to define large virtual libraries of theoretically feasible chemical structures or exploit them for de novo design purposes and (re)scaffold-hopping are ongoing.…”

Section: Introductionmentioning

confidence: 99%

The Proximal Lilly Collection: Mapping, Exploring and Exploiting Feasible Chemical Space

Nicolaou

Watson

Hong

et al. 2016

J. Chem. Inf. Model.

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Venturing into the immensity of the small molecule universe to identify novel chemical structure is a much discussed objective of many methods proposed by the chemoinformatics community. To this end, numerous approaches using techniques from the fields of computational de novo design, virtual screening and reaction informatics, among others, have been proposed. Although in principle this objective is commendable, in practice there are several obstacles to useful exploitation of the chemical space. Prime among them are the sheer number of theoretically feasible compounds and the practical concern regarding the synthesizability of the chemical structures conceived using in silico methods. We present the Proximal Lilly Collection initiative implemented at Eli Lilly and Co. with the aims to (i) define the chemical space of small, drug-like compounds that could be synthesized using in-house resources and (ii) facilitate access to compounds in this large space for the purposes of ongoing drug discovery efforts. The implementation of PLC relies on coupling access to available synthetic knowledge and resources with chemo/reaction informatics techniques and tools developed for this purpose. We describe in detail the computational framework supporting this initiative and elaborate on the characteristics of the PLC virtual collection of compounds. As an example of the opportunities provided to drug discovery researchers by easy access to a large, realistically feasible virtual collection such as the PLC, we describe a recent application of the technology that led to the discovery of selective kinase inhibitors.

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CROSS: An Efficient Workflow for Reaction-Driven Rescaffolding and Side-Chain Optimization Using Robust Chemical Reactions and Available Reagents

Cited by 8 publications

References 59 publications

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

ChemoDOTS: a web server to design chemistry-driven focused libraries

The Proximal Lilly Collection: Mapping, Exploring and Exploiting Feasible Chemical Space

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