Identification of readily available pseudo-natural products

Pahl, Axel; Grygorenko, Oleksandr O.; Kondratov, Ivan S.; Waldmann, Herbert

doi:10.1039/d4md00310a

Cited by 1 publication

(8 citation statements)

References 36 publications

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“…The full dataset after removal of molecules filtered by the PNP algorithm 17 (predominantly molecular weight >1000 and presence of uncommon elements) contained 3173 unique clinical compounds and 388,027 unique reference compounds. There were 9644 clinical compound-target pairs and 596,341 reference compound-target pairs, covering 2285 targets.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is our experience that recognizing a PNP structure and knowing those NP fragment combinations that are nonbiosynthetic are often not intuitive or straightforward. Applying the available PNP algorithm 17 in advance of synthesis is a necessary step. In designing new PNPs, synthetic challenges are likely to arise; the investment required needs to be balanced against the accumulating evidence supporting their biological relevance, clinical dominance, and untapped potential.…”

Section: Discussionmentioning

confidence: 99%

“…However, we note that thousands of PNPs are now available from commercial sources, such that PNP libraries can readily be established without extensive synthesis efforts. 17 Further extension to consider additional NP ring systems and acyclic frameworks 29 , 30 is also possible.…”

Section: Discussionmentioning

confidence: 99%

“… 18 , 19 Thousands of PNPs are available from commercial sources, and a PNP screening library can be readily established. 17 …”

Section: Introductionmentioning

confidence: 99%

“…Pseudo-NPs (PNPs) provide a new approach to quantifying the appearance of NP structural elements. − PNPs contain low-molecular-weight NP fragments, selected from a designed library, which are connected in defined ways not currently known to be achievable by biosynthetic pathways. The PNP concept has been validated by its appearance in the literature , and by the design of several new classes of biologically active compounds. , Thousands of PNPs are available from commercial sources, and a PNP screening library can be readily established …”

Section: Introductionmentioning

confidence: 99%

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Occurrence of “Natural Selection” in Successful Small Molecule Drug Discovery

Heinzke,

Pahl,

Zdrazil

et al. 2024

J. Med. Chem.

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Published compounds from ChEMBL version 32 are used to seek evidence for the occurrence of "natural selection" in drug discovery. Three measures of natural product (NP) character were applied, to compare time-and target-matched compounds reaching the clinic (clinical compounds in phase 1−3 development and approved drugs) with background compounds (reference compounds). Pseudo-NPs (PNPs), containing NP fragments combined in ways inaccessible by nature, are increasing over time, reaching 67% of clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 clinical versus reference compounds. The majority of target classes show increased clinical compound NP character versus their reference compounds. Only 176 NP fragments appear in >1000 clinical compounds published since 2008, yet these make up on average 63% of the clinical compound's core scaffolds. There is untapped potential awaiting exploitation, by applying nature's building blocks� "natural intelligence"�to drug design.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%