Structural simplification: an efficient strategy in lead optimization

Wang, Shengzheng; Dong, Guoqiang; Sheng, Chunquan

doi:10.1016/j.apsb.2019.05.004

Cited by 67 publications

(49 citation statements)

References 133 publications

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“…Structural biology plays an important role in early-stage drug discovery, as the elucidation of the binding modes of "hit" compounds can provide essential information to drive downstream, lead compound development (de Kloe et al 2009;Wang et al 2019). While crystallization of proteins relies on a number of sample properties, with sample purity and homogeneity generally agreed to be the key determining factors (Giegi et al 1994;Dale et al 2003;Ericsson et al 2006), thermal stability has also been shown to be a critical parameter in a successful outcome during crystallogenesis.…”

Section: The Use Of Dsf In Buffer Screening and Optimization Of Protementioning

confidence: 99%

Theory and applications of differential scanning fluorimetry in early-stage drug discovery

2020

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Differential scanning fluorimetry (DSF) is an accessible, rapid, and economical biophysical technique that has seen many applications over the years, ranging from protein folding state detection to the identification of ligands that bind to the target protein. In this review, we discuss the theory, applications, and limitations of DSF, including the latest applications of DSF by ourselves and other researchers. We show that DSF is a powerful high-throughput tool in early drug discovery efforts. We place DSF in the context of other biophysical methods frequently used in drug discovery and highlight their benefits and downsides. We illustrate the uses of DSF in protein buffer optimization for stability, refolding, and crystallization purposes and provide several examples of each. We also show the use of DSF in a more downstream application, where it is used as an in vivo validation tool of ligand-target interaction in cell assays. Although DSF is a potent tool in buffer optimization and large chemical library screens when it comes to ligand-binding validation and optimization, orthogonal techniques are recommended as DSF is prone to false positives and negatives.

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Section: The Use Of Dsf In Buffer Screening and Optimization Of Protementioning

confidence: 99%

Theory and applications of differential scanning fluorimetry in early-stage drug discovery

2020

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“…Therefore, different approaches are required to develop a target-specific anticancer treatment. The structural simplification of natural products is one of the well-known strategies to improve pharmacokinetic profiles and to reduce side effects [ 16 ]. Initially, anticancer activity of the first simplified spiroisoxazolines 4 and 5 ( Figure 2 ) was reported in Ehrlich ascites tumor cells in mice [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs

et al. 2021

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Marine-originated spirocyclic bromotyrosines are considered as promising scaffolds for new anticancer drugs. In a continuation of our research to develop potent and more selective anticancer compounds, we synthesized a library of 32 spirocyclic clavatadine analogs by replacing the agmatine, i.e., 4-(aminobutyl)guanidine, side chain with different substituents. These compounds were tested for cytotoxicity against skin cancer using the human melanoma cell line (A-375) and normal human skin fibroblast cell line (Hs27). The highest cytotoxicity against the A-375 cell line was observed for dichloro compound 18 (CC50 0.4 ± 0.3 µM, selectivity index (SI) 2). The variation of selectivity ranged from SI 0.4 to reach 2.4 for the pyridin-2-yl derivative 29 and hydrazide analog of 2-picoline 37. The structure–activity relationships of the compounds in respect to cytotoxicity and selectivity toward cancer cell lines are discussed.

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“…A number of structurally simpler derivatives, based on two‐ring scaffolds, were also synthesized with the aim of gaining information on the minimal pharmacophore features [6] of the compounds under examination. The effects of such a molecular pruning on target interactions are shown in Table 2 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Dantrolene‐Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases

et al. 2021

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Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC 50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/ acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.

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Structural simplification: an efficient strategy in lead optimization

Cited by 67 publications

References 133 publications

Theory and applications of differential scanning fluorimetry in early-stage drug discovery

Theory and applications of differential scanning fluorimetry in early-stage drug discovery

Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs

Synthesis and Biological Evaluation of Dantrolene‐Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases

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