Fragment-to-Lead Medicinal Chemistry Publications in 2016

Johnson, Christopher N.; Erlanson, Daniel A.; Jahnke, Wolfgang; Mortenson, Paul N.; Rees, David C.

doi:10.1021/acs.jmedchem.7b01298

Cited by 51 publications

(67 citation statements)

References 53 publications

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“…The similarity paradox claims that even the smallest structural change can result in the substantial activity changes; therefore; the regularity will rather be surprising. In Figure 1 we reanalyzed the F2L data (27)(28)(29) plotting the change of AC 50 related values of ∆pAC 50, ∆LE or ∆pPLE in the course of F2L conversion as a function of HAC of the original fragments. As expected there is no correlation between the ∆pAC 50, and ∆pPLE and HAC for fragments.…”

Section: Resultsmentioning

confidence: 99%

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Scoring ligand efficiency

Polański¹,

Duszkiewicz²,

Pedrys³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Ligand efficiency (LE) is a molecular descriptor that probes the ratio of potency vs. heavy atom count (HAC). As an estimator of drug candidates, LE emphasizes a low heavy atom count more than potency. The objective was to design a novel transform where potency and the HAC would be balanced more evenly. A series of novel descriptors SCORE were defined to evaluate the co-influence of potency and the HAC. In particular, the product ligand efficiency (PLE) was designed and tested using the data of the ChEMBL, PubChem as well as the selected series of drugs and drug-fragments.

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Section: Resultsmentioning

confidence: 99%

“…The dependence of the difference between the lead and fragment potency measured as ∆pAC 50 (a) , ∆pPLE (b) or ∆LE (c) as a function of HAC during F2L development reported in Journal of Medicinal Chemistry 2015-2017, indicated both for fragments and leads. Data after(27)(28)(29) …”

mentioning

confidence: 99%

Scoring ligand efficiency

Polański¹,

Duszkiewicz²,

Pedrys³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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“…The structural moieties that make key interactions with a target protein in existing cocrystal structures can be employed separately in similarity or substructure database searches for fragments, which can then be merged or linked together to generate new ligands. Fragments generally have weak affinities with target proteins and pose significant challenges for screening through biophysical techniques [50,51]. The two energy evaluation methods in the virtual drug screening tool have the accuracy to solve the problem of fragment screening.…”

Section: Virtual Drug Screeningmentioning

confidence: 99%

Discovery of New CDK8 ligands with a Novel Virtual Drug Screening Tool

Chen¹,

Ren

2018

Preprint

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Selective inhibition of CDK8 could be a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. As compared with type I ligands, binding of a type II compound often achieves longer residence time. We developed a novel virtual drug screening package which takes advantage of two energy evaluation methods: Superposition and Single-Point Energy Evaluation, and VM2 free energy calculation, and applied it to the discovery of new CDK8 type II ligands. In this research we analyzed binding thermodynamics of 11 published CDK8 type II ligands, and extracted the key binding information to assist virtual drug screening for new ligands. The free energy and MD calculations on the reference CDK8-ligand complexes revealed the important factors in the binding. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety we implemented virtual drug screening and singled out three compounds for bio-assay testing. The ranking from the experimental result for the three compounds is completely consistent with the predicted rankings by both energy evaluation methods. A potent drug-like compound was discovered to have a K d value of 42.5 nM with CDK8, which is comparable to the most potent reference ligands and provided a good starting point to design and synthesize a series of highly selective and potent CDK8 ligands. Therefore, our novel virtual drug screening package is accurate and efficient enough to be used in drug design projects. We believe this work has significant impact to the field of drug discovery.

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“…This scenario is by no means rare: based on reviews of the 2015 and 2016 fragment-to-lead medicinal chemistry publications (Johnson et al, 2017a(Johnson et al, , 2017b, 7 out of 27 (2015), and 8 out of 28 (2016) successful fragment-based lead discovery campaigns did not have X-ray structures for the initial fragment hits bound to their targets. Furthermore, some of the most prominent FBDD examples, such as the discovery of venetoclax (Souers et al, 2013), could not take advantage of early crystal structures and had to follow alternative strategies to advance fragment hits.…”

Section: Introductionmentioning

confidence: 99%

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Erlanson

Davis

Jahnke

2019

Cell Chemical Biology

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104

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Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization. Essentially, all models are wrong, but some are useful.

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Fragment-to-Lead Medicinal Chemistry Publications in 2016

Cited by 51 publications

References 53 publications

Scoring ligand efficiency

Scoring ligand efficiency

Discovery of New CDK8 ligands with a Novel Virtual Drug Screening Tool

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

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