The Time and Place for Nature in Drug Discovery

Abstract

The case for a renewed focus on Nature in drug discovery is reviewed; not in terms of natural product screening, but how and why biomimetic molecules, especially those produced by natural processes, should deliver in the age of artificial intelligence and screening of vast collections both in vitro and in silico. The declining natural product-likeness of licensed drugs and the consequent physicochemical implications of this trend in the context of current practices are noted. To arrest these trends, the logic of seeking new bioactive agents with enhanced natural mimicry is considered; notably that molecules constructed by proteins (enzymes) are more likely to interact with other proteins (e.g., targets and transporters), a notion validated by natural products. Nature’s finite number of building blocks and their interactions necessarily reduce potential numbers of structures, yet these enable expansion of chemical space with their inherent diversity of physical characteristics, pertinent to property-based design. The feasible variations on natural motifs are considered and expanded to encompass pseudo-natural products, leading to the further logical step of harnessing bioprocessing routes to access them. Together, these offer opportunities for enhancing natural mimicry, thereby bringing innovation to drug synthesis exploiting the characteristics of natural recognition processes. The potential for computational guidance to help identifying binding commonalities in the route map is a logical opportunity to enable the design of tailored molecules, with a focus on “organic/biological” rather than purely “synthetic” structures. The design and synthesis of prototype structures should pay dividends in the disposition and efficacy of the molecules, while inherently enabling greener and more sustainable manufacturing techniques.

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

“…For representative benzyl ether 5a, 1D Nuclear Overhauser Effect (NOE) NMR analyses indeed indicate endo stereochemistry. As a further confirmation, the major 1 H and 13 C NMR signals for 5a are identical to those reported for the endo isomer [53], while the minor 13 C NMR signals in 5a match those reported for the exo isomer ( 1 H NMR data have not been reported for the exo isomer) [57]. Assignment of the stereochemistry in N-analogs proved to be more challenging, and success varied for several reasons: (1) As the d.r.…”

“…Pyrolysis (heating) of biomass polymers has the potential to provide smaller and versatile offspring molecules [ 9 , 10 ] that may retain several fingerprints of the parents’ molecular properties. That is, depending on the biomass resource and pyrolysis conditions used, the offspring molecules can themselves be considerably biogenic, and biogenic molecules originating from natural products have been shown to have advantageous properties in drug research [ 11 , 12 , 13 ]. As a result of technological advances in pyrolysis processing, biomass-derived products are only now becoming readily available.…”

Mining the Protein Data Bank to inspire fragment library design

“…A total of 38 fragments show a logP in the 0-2 range, yet there are also 50 hydrophilic fragments (logP <0). The combinations of lipophilicity and molecular weight which are little explored by recently developed synthetic oral drugs should not be overlooked since they may correspond to molecules of therapeutic interest such as natural products (e.g., antibiotics) (Young et al, 2022). Thus, we did not exclude hydrophilic fragments from the analysis.…”

The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development

“… 11 , 12 , 18 − 27 As such, this perspective does not aim to be comprehensive but rather highlight the current state-of-the-art of preparative enzymatic synthesis in an industrial setting. Therefore, the use of biocatalysis for small-scale pharmaceutical metabolite synthesis, 28 lead diversification, 15 , 16 , 23 , 24 bioconjugation, 29 and selective protein modification 30 − 32 will not be focused upon in this article.…”