Abstract
Natural products are the result of Nature’s exploration of biologically relevant chemical space through evolution and an invaluable source of bioactive small molecules for chemical biology and medicinal chemistry. Novel concepts for the discovery of new bioactive compound classes based on natural product structure may enable exploration of wider biologically relevant chemical space. The pseudo-natural product concept merges the relevance of natural product structure with efficient exploration of chemical space by means of fragment-based compound development to inspire the discovery of new bioactive chemical matter through de novo combination of natural product fragments in unprecedented arrangements. The novel scaffolds retain the biological relevance of natural products but are not obtainable through known biosynthetic pathways which can lead to new chemotypes that may have unexpected or unprecedented bioactivities. Herein, we cover the workflow of pseudo-natural product design and development, highlight recent examples, and discuss a cheminformatic analysis in which a significant portion of biologically active synthetic compounds were found to be pseudo-natural products. We compare the concept to natural evolution and discuss pseudo-natural products as the human-made equivalent, i.e. the chemical evolution of natural product structure.
Highlights
The importance of small molecules that can perturb biological systems in a controlled fashion is underpinned by their successful applications in chemical biology[1] and medicine.[2]
The complexity to diversity approach employs “end point” NPs as divergent intermediates and chemically extends biosynthetic pathways by distorting the scaffolds of NPs through ring distortion reactions (Figure 1a).[29−31] The resulting compound collections have diverse scaffolds that are distinct from the parent NP but retain the complexity of and biological relevance to NPs; the concept may be limited by the finite number of possible starting points. While all of these methods have been successful in providing compound libraries that are enriched in bioactivities, each has, to some extent, limitations that hinder wider exploration of biologically relevant chemical space. To expand beyond these limitations while still retaining relevance to NPs, we have developed the concept of pseudo-natural products.[19,32−34] The principle merges the biological relevance of NPs with the rapid accessibility to diverse chemical space of fragment-based discovery
The pseudo-NP concept is intended to overcome limitations that are inherent to other NP-inspired molecular design principles and explore new areas of biologically relevant chemical space
Summary
The importance of small molecules that can perturb biological systems in a controlled fashion is underpinned by their successful applications in chemical biology[1] and medicine.[2]. By selecting more sp3-enriched and oxygen-containing NP fragments as combination partners and employing a broader distribution of fusion patterns, future pseudo-NP collections may more closely mimic properties Nature has instilled in NPs; i.e., they will be more NP-like.[71] novel arrangements of NP fragments will deviate from the current NP structure to afford compound classes that will explore new areas of chemical space while retaining the biological relevance of NPs. Beyond having Nature guide pseudo-NP design, the choice of fragment combination may be influenced by evaluating the biological diversity of current pseudo-NPs. If the arrangement of a common set of fragments results in diverse biological profiles, the fragments could be classified as nondominating and may be good candidates for future combinations.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
