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Identification of readily available pseudo-natural products.

ABSTRACT: Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synthesis programs. We employed an improved version of the previously reported natural product fragment combination (NPFC) tool to analyze the full library of 3.5 M synthetic small molecules and screening libraries from Enamine for PNP content, assessed the spatial complexity of Enamine-PNPs using the recently developed normalized spatial score (nSPS) and evaluated the bioactivity of a selected subset of Enamine-PNPs in the unbiased morphological cell painting assay. A major fraction (32%; 1.1 million compounds) of the Enamine library are PNPs which contain a significant number of compounds with unexpected and probably new bioactivity.

SUBMITTER: Pahl A

PROVIDER: S-EPMC11324060 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Identification of readily available pseudo-natural products.

Pahl Axel A Grygorenko Oleksandr O OO Kondratov Ivan S IS Waldmann Herbert H

RSC medicinal chemistry 20240704 8

Pseudo-natural products (PNPs) combine fragments derived from NPs in ways that are not found in nature, and may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. PNPs have increasingly been explored in recent drug discovery programs, and are strongly enriched in clinical compounds. We describe how a large number of structurally different PNPs can be accessed readily and without the need to execute labor- and time intensive synt ...[more]

PMID: 39149091

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Project description:BackgroundMalignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. Unfortunately, the specific medicine dantrolene is not readily available in many countries including China. The aim of this study was to find the characteristics of malignant hyperthermia under the situation that dantrolene is not readily available.MethodsThe cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. The inclusion criteria were the MH episodes only related to anesthesia. The exclusion criteria were dubious MH episodes only caused by Ketamine administration or MH episodes irrelevant to anesthesia. Independent samples t-test and Pearson's chi-squared test were applied to assess the difference between the survived and death cases.ResultsNinety-two cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. Median (IQR [range]) age was 18.5 (11.8-37.0 [0-70.0]) years. Compared with the survived cases, the death cases had higher maximum end-tidal partial pressure of CO2 (P = 0.033), the maximum arterial partial pressure of CO2 (P = 0.006), temperature first measured when the patient was first discovered abnormal (P = 0.012), and maximum temperature (P < 0.001). Besides, the death cases had less minimum pH (P < 0.001) and higher potassium (P < 0.001) and were more likely to have coagulation disorders (p = 0.018). Concerning treatment, cases used furosemide (P = 0.024), mannitol (P = 0.029), blood purification treatment (P = 0.017) had the advantage on the outcome. Creatine phosphokinase, myoglobin, and MB isoenzyme of creatine phosphokinase differed greatly among cases during the first week. 43 (46.7%) cases had congenital diseases. 12 (13.0%) cases were reported with abnormal laboratory test results or abnormal signs that are possibly relevant before anesthesia.ConclusionsIn countries that dantrolene is not readily available, early warning, diagnosis, and prompt effective therapies are crucial for MH patients to survive.

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Identification of readily available pseudo-natural products.

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Identification of readily available pseudo-natural products.

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