Morphological subprofile analysis for bioactivity annotation of small molecules

Pahl, Axel; Schölermann, Beate; Lampe, Philipp; Rusch, Marion; Dow, Mark; Hedberg, Christian; Nelson, Adam; Sievers, Sonja; Waldmann, Herbert; Ziegler, Slava

doi:10.1016/j.chembiol.2023.06.003

“…By comparing the profiles of active compounds to those of reference compounds with annotated activities, target hypotheses can be derived (details in the “Experimental Section” section). In addition, a similarity to 13 biological clusters thus far can be determined by comparing CP subprofiles. , …”

Section: Resultsmentioning

confidence: 99%

Illuminating Dark Chemical Matter Using the Cell Painting Assay

Pahl,

Liu,

Patil

et al. 2024

J. Med. Chem.

Self Cite

3

0

View full text Add to dashboard Cite

Screening for small-molecule modulators of diseaserelevant targets and phenotypes is the first step on the way to new drugs. Large compound libraries have been synthesized by academia and, particularly, pharmaceutical companies to meet the need for novel chemical entities that are as diverse as possible. Screening of these compound libraries revealed a portion of small molecules that is inactive in more than 100 different assays and was therefore termed "dark chemical matter" (DCM). Deorphanization of DCM promises to yield very selective compounds as they are expected to have less off-target effects. We employed morphological profiling using the Cell Painting assay to detect bioactive DCM. Within the DCM collection, we identified bioactive compounds and confirmed several modulators of microtubules, DNA synthesis, and pyrimidine biosynthesis. Profiling approaches are, therefore, powerful tools to probe compound collections for bioactivity in an unbiased manner and are particularly suitable for deorphanization of DCM.

show abstract

“…the target or MoA most often associated with the compound, [52] as recently demonstrated for the NUAK1 inhibitor HTH-01-015. [49] ClogP and bpKa were calculated for the pseudo-NPs and the MIA NP reference set. Most of the pseudo-NPs (Class A = 98 %, Class B = 85 %) lie within the physicochemical parameters defined for potentially lysosomotropic compounds (Figure S14) which correlates to their high biosimilarity to the LCH cluster (Class A = 100 %, Class B = 46 %).…”

Section: Methodsmentioning

confidence: 99%

“…To facilitate the annotation of several compounds simultaneously, we have introduced a CPA subprofile analysis. [49] bioactivity clusters of compounds that share similar CPA profiles are identified, and subprofiles are produced by reducing the number of profile features to only those that are shared within a bioactivity cluster. The median features of the resulting truncated profiles are taken, resulting in a profile that is representative of a particular bioactivity cluster.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

Xie,

Pahl,

Krzyzanowski

et al. 2023

Angew Chem Int Ed

Self Cite

3

0

View full text Add to dashboard Cite

Monoterpene indole alkaloids (MIAs) are endowed with high structural and spacial complexity and characterized by diverse biological activities. Given this complexity‐activity combination in MIAs, rapid and efficient access to chemical matter related to and with complexity similar to these alkaloids would be highly desirable, since such compound classes might display novel bioactivity. We describe the design and synthesis of a pseudo‐natural product (pseudo‐NP) collection obtained by the unprecedented combination of MIA fragments through complexity‐generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatic analyses revealed that both the pseudo‐NPs and the MIAs reside in a unique and common area of chemical space with high spacial complexity‐density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo‐NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo‐NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with.

show abstract

“…To facilitate the annotation of several compounds simultaneously, we have introduced a CPA subprofile analysis. [49] Briefly, bioactivity clusters of compounds that share similar CPA profiles are identified, and subprofiles are produced by reducing the number of profile features to only those that are shared within a bioactivity cluster. The median features of the resulting truncated profiles are taken, resulting in a profile that is representative of a particular bioactivity cluster.…”

Section: Biological Evaluation Of the Pseudo-np Collectionmentioning

confidence: 99%

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

Xie,

Pahl,

Krzyzanowski

et al. 2023

Angewandte Chemie

Self Cite

0

View full text Add to dashboard Cite

Monoterpene indole alkaloids (MIAs) are endowed with high structural and spacial complexity and characterized by diverse biological activities. Given this complexity‐activity combination in MIAs, rapid and efficient access to chemical matter related to and with complexity similar to these alkaloids would be highly desirable, since such compound classes might display novel bioactivity. We describe the design and synthesis of a pseudo‐natural product (pseudo‐NP) collection obtained by the unprecedented combination of MIA fragments through complexity‐generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatic analyses revealed that both the pseudo‐NPs and the MIAs reside in a unique and common area of chemical space with high spacial complexity‐density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo‐NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo‐NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with.

show abstract

Morphological subprofile analysis for bioactivity annotation of small molecules

Cited by 18 publications

References 41 publications

Illuminating Dark Chemical Matter Using the Cell Painting Assay

Illuminating Dark Chemical Matter Using the Cell Painting Assay

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

Contact Info

Product

Resources

About