Drug Discovery and Development

Introduction

Chemistry has played an integral part in drug discovery and development and will continue to be essential in addressing the global health challenges we face as a society. The inspiration for molecular design has often come from Nature, with Natural Products providing bioactive scaffolds that can be structurally modified to enhance activity and improve selectivity. Initially, small molecule drugs such as salicylic acids, penicillins, or taxols set the foundation, complemented later by non-natural scaffolds identified through screening extensive synthetic compound libraries against targets. In recent years, more complex biopharmaceuticals, including nucleic acids, carbohydrates, and proteins, have become more prominent, with about 50 out of 100 of the top brand name drugs by retail sales in 2022 falling under the category of “biologics” or “new modalities”.¹

In this virtual issue, we have selected 26 recently published works in Drug Discovery and Development from issues of JACS Au, including Articles, Letters, and Perspectives. Readers will find in this collection of papers an exciting and active field of research that is broad and highly interdisciplinary, ranging from metal-based methodologies to natural product (bio)synthesis, the development of chemical toolboxes for screening and target identification, to advancements in biologics and drug delivery systems.

Small Molecules for Drug Discovery

Developing stereoselective synthetic methods for pharmacophores is still of great interest, and there is a particular gap for noncarbon chiral centers. A perspective by Zhang et al. (DOI: 10.1021/jacsau.2c00626) summarizes the strategies available for making sulfur(IV) and (VI) stereogenic centers in their enantiopure form, an area has been underexplored and needs new strategies. Similarly, the perspective by Van Giesen et al. (DOI: 10.1021/jacsau.2c00481) highlights the need for the stereoselective methods to chiral phosphorothioate linkages, which are often found in RNA antisense and interference oligomers instead of native phosphodiester bonds to improve metabolic stability. They suggest that biocatalysis is an attractive methodology for stereoselective phosphate thio-ester bond formation.

Natural products continue to provide scaffolds for drug entities and one recent example is provided by Guo et al. (DOI: 10.1021/jacsau.2c00600) who identified Fargesone A from a high-throughput screen of the Farnesoid X receptor, a key regulator in liver disease. Biomimetic chemical synthesis was used to develop a scalable production of Fargesone A for in vivo studies providing the foundation for a potential therapy for liver diseases. Felber et al. (DOI: 10.1021/jacsau.2c00448) focus on the DNA-alkylating cytotoxins of the duocarmycin class in their perspective, looking back at its 40 years of history. It is interesting to see the long development from early SAR studies to prodrug strategies and the recent FDA-approval of an antibody-duocarmycin conjugate. Starting from a natural product in drug discovery can provide challenges for scalable production, in particular if chemical routes are not efficient. Huang et al. (DOI: 10.1021/jacsau.2c00594) address such issues by studying the biosynthesis of the polyketide class of Bipentaromycins, which contain unusual cyclic head-to-tail dimeric scaffolds with potent activity. Using a number of biochemical tools, including isotope labeling, heterologous expression and modeling they have identified the enzymes involved in the key biosynthetic steps, providing biochemical routes to active dimeric pharmacophores for further study.

Against recent impressive developments in the synthesis and screening of massive synthetic chemical libraries in medicinal chemistry, the perspective by Young et al. (DOI: 10.1021/jacsau.2c00415) makes a case for a renewed focus on natural motifs and processes. The authors argue that the design and synthesis of more “organic/biological” rather than “synthetic structures” would pay dividends in efficacy while also inherently enabling greener and more sustainable manufacturing techniques.

The targetted covalent inhibition of proteins by modifying side chains such as cysteines or lysines has gained recognition as an attractive strategy for treating diseases such as cancer or viral infections. Huang et al. (DOI: 10.1021/jacsau.1c00420) have used chloro-mercury model compounds to target cysteines in the DEDDh family of exonucleases. Their observation of allosteric deactivation through binding distal to the active and substrate-binding site provides evidence for the existence of multiple pathways for exonuclease inhibition and has promise for reducing off-target effects.

Small synthetic molecules are increasingly useful as probes to understand complex biological pathways. For example, Coelho et al. (DOI: 10.1021/jacsau.3c00113) use cell-penetrating dynamic covalent cascade exchangers to inhibit cell migration. This study elegantly demonstrates that these reversible covalent inhibitors target the rich disulfide exchange chemistry of integrins and shed some light on the mechanism of thiol-mediated uptake of matter into cells. Dzijak et al. (DOI: 10.1021/jacsau.0c00053) developed bioorthogonal reagents that can be used for organelle-specific prodrug activation, providing chemical tools for manipulating biological processes in the cell through abiotic chemistry. Gama-Brambila et al. (DOI: 10.1021/jacsau.1c00007) use perfluoro aromatic labels as proximity probes to develop a toolbox for labeling and degrading engineered CAS proteins in living cells. Proximity effects are also used by Tang et al. (DOI: 10.1021/jacsau.3c00195) in their study of proteolysis-targetting chimeras (PROTACs), uncovering kinetic characteristics and reaction specificity using advanced computational methods of analysis.

Membrane disrupting molecules have been highly effective antimicrobial agents, such as the antifungal agent Amphotericin B or the antibacterial Polymyxin B. For the successful development of such drugs, it is important to fully understand all aspects of target interaction, and the perspective by Regan (DOI: 10.1021/jacsau.0c00037) considers the importance of the aggregation state of the drug molecule. The perspective cites evidence that monomers are more selective than the corresponding aggregates of the membrane-disrupting molecule.

New Modalities

While small molecules still play a key role in drug development, larger biomacromolecules such as nucleic acids, polysaccharides, proteins and mixed conjugates are forming a significant section of pharmaceutical chemistry and are often described as “new modalities”. The Perspectives by Debon et al. (DOI: 10.1021/jacsau.2c00617) and Van Giesen et al. (DOI: 10.1021/jacsau.2c00481) provide an excellent overview of the challenges of producing new modalities at scale and purity. Key chemical transformations involve biorthogonal conjugation strategies–for example to link payloads to antibodies and selective polymerization reactions in oligonucleotides and peptides. The authors make the case for using biocatalysis, citing successes but also reviewing the many challenges that still remain to be solved in the field. Shmool et al. (DOI: 10.1021/jacsau.2c00356) focus on a different aspect of protein therapeutics–the high drop-outs from drug pipelines due to protein instability, in particular aggregation. A predictive tool for protein aggregation propensity and thermodynamic stability is developed based on ionic liquids, which can identify protein formulations that significantly increase storage time and should lead to reducing the number of failures in pipeline.

A few reports in our collection provide some exciting examples of applications of new modalities to solve unmet health needs. Lin et al. (DOI: 10.1021/jacsau.0c00057) describe a strategy to use broadly neutralizing antibodies to combat cannabinoid use disorder, providing tools to address the expanding cannabinoid crisis. Zhang et al. (DOI: 10.1021/jacsau.2c00537) aim to overcome potential serious side-effects of the clinical anticoagulant pentasaccharide Fondaparinux by tagging it with biotin and demonstrating neutralization, thus providing an antidote when required. Hartweg et al. (DOI: 10.1021/jacsau.1c00255) have developed a synthetic strategy of iterative growth to give facile access to glycomacromolecules that can target carbohydrate ligands on immune cell surfaces with high selectivity. Cai et al. (DOI: 10.1021/jacsau.2c00674) present the application of DNA-encoded chemical libraries to find biased agonists of G protein-coupled receptors in living cells. The key is the use of a split complementation approach that allows for the selective purification of ligands that both bind and induce dimerization activity in the receptor.

Drug Delivery

The application of nanomaterial-based drug delivery systems to deliver both small molecules and new modalities in a highly targetted manner to cells and tissues is a very attractive concept for biomedicine, but is still an unmet challenge. Boehnke et al. (DOI: 10.1021/jacsau.1c00313) provide an interesting perspective on this important field and discuss recent work on leveraging library-based nanoparticle screens to obtain data on structure–function relationships of delivery systems and thus guide carrier design.

Innovative Metal-Based Methodologies for Drug Design and Synthesis

Recently described metal-based methodologies offer novel and innovative approaches to drug synthesis, addressing key challenges in the field of medicinal chemistry. The iridium-catalyzed directed C–H amination methodology described by Weis et al, utilizing high-throughput experimentation, not only streamlines the drug discovery process but also provides valuable reaction guidelines through informer library strategies (DOI: 10.1021/jacsau.2c00039). There is also a growing importance of innovative approaches in the synthesis of isotopically labeled compounds, crucial for preclinical studies and quantification purposes. The Rh nanoparticle catalysis method, developed by Levenier et al. allows for in situ generation, enabling the labeling of prevalent substructures (DOI: 10.1021/jacsau.1c00503). This approach, using commercially available rhodium dimer under deuterium or tritium gas, offers an easy-to-implement one-step synthesis for deuterated pharmaceuticals and high molar activity tritiated drug analogs. Additionally, the Cu-catalyzed aryl alkyne transfer hydrodeuteration method, reported by Soane et al. provides a regio- and chemoselective strategy for precisely deuterating aryl alkanes at the benzylic position, showcasing high selectivities and minimal isotopic impurities (DOI: 10.1021/jacsau.3c00053). Together, these methodologies present advanced solutions in labeling synthesis with potential applications in drug development.

The integration of photocatalysis and transition-metal catalysis offers a versatile and environmentally friendly platform for drug synthesis, with a focus on meta-oxygenation of diverse arenes (DOI: 10.1021/jacsau.3c00231). Ali et al. have demonstrated that operating through a radical pathway, this innovative approach provides an efficient and regioselective protocol under mild conditions, showcasing its broad applicability to different substrates and substituents.

Chiral molecules are vital in pharmaceuticals, with current research emphasizing swift synthetic methods to access diverse chiral compounds and explore their unique properties. Gu et al. introduce an efficient method for enantioanalysis of N-heterocycles, highlighting the pivotal role of a chiral 19F-labeled palladium probe in synthesizing chiral molecules. The method relies on dynamic binding between analytes and the probe, producing distinctive 19F NMR signals for each enantiomer (DOI: 10.1021/jacsau.2c00661).

Metallodrugs

As discussed in the perspective of Frei et al, metal complexes play a crucial role in the search for novel antifungal drugs, addressing the urgent need for alternatives due to the rise of resistant fungal strains (DOI: 10.1021/jacsau.2c00308). Out of 1039 metal-containing compounds screened, 20.9% displayed antimicrobial activity, contrasting to only 1.1% of over 300 000 purely organic molecules tested. Notably, 8.7% of the metal compounds exhibited antifungal activity without cytotoxicity to mammalian cells or hemolytic properties. These findings underscore the potential of metal-based compounds in diversifying drug development for infectious diseases. Addressing intracellular iron bioavailability is a potential strategy for developing broad-spectrum anticancer drugs, given iron’s vital role in cancer proliferation and metastasis (DOI: 10.1021/jacsau.1c00078). Gaur et al. specifically explore inhibiting human ribonucleotide reductase (RNR), a key enzyme in DNA replication and repair, using intracellular iron chelators with a transmetalative approach. Titanium-based complexes tested in the study demonstrated effective attenuation of RNR activity and a promising synergistic effect when combined with cisplatin.

Future Outlook

The 26 papers published in JACS Au focusing on drug design and development over the last years offer an attractive snapshot of the very diverse activities within this field. Chemists continue to play a key role, although the landscape is increasingly shaped by our expanding molecular understanding of Nature. Core tools such as synthetic chemistry, analysis and computational methods persist, indicating a need for ongoing innovation.

The pharmaceutical domain is undergoing an evident shift from small molecules to larger biomacromolecules, driven not only by clinical demands but also by the rapid advancements in structural and chemical biology tools allowing very fast structural analysis of even complex molecules as well as their production and manipulation. Bioconjugation and abiotic chemistry have gained significance in selective labeling both in vitro and in vivo and in producing successful drugs, such as antibody-drug conjugates and RNA.

As the complexity of targets grows, using biocatalysis for bioorthogonal and biocompatible selective transformations emerges as an attractive complementary technique to traditional purely chemical synthetic methods. The most exciting and successful strategies seem to be built on a deep understanding of both the chemistry and biology inherent in drug design and development.

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.