Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece.

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.

Interrogating Aptamer Chemical Space Through Modified Nucleotide Substitution Facilitated by Enzymatic DNA Synthesis.

Chemical modification of aptamers is an important step to improve their performance and stability in biological media. This can be performed either during their identification (mod-SELEX) or after the in vitro selection process (post-SELEX). In order to reduce the complexity and workload of the post-SELEX modification of aptamers, we have evaluated the possibility of improving a previously reported, chemically modified aptamer by combining enzymatic synthesis and nucleotides bearing bioisosteres of the parent cubane side-chains or substituted cubane moieties. This method lowers the synthetic burden often associated with post-SELEX approaches and allowed to identify one additional sequence that maintains binding to the PvLDH target protein, albeit with reduced specificity. In addition, while bioisosteres often improve the potency of small molecule drugs, this does not extend to chemically modified aptamers. Overall, this versatile method can be applied for the post-SELEX modification of other aptamers and functional nucleic acids.

An update on late-stage functionalization in today's drug discovery.

INTRODUCTION: Late-stage functionalization (LSF) allows for the introduction of new chemical groups toward the end of a synthetic sequence, which means new molecules can be rapidly accessed without laborious de novo chemical synthesis. Over the last decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, affording benefits such as efficient access to diverse libraries to explore structure-activity relationships and the improvement of physicochemical and pharmacokinetic properties. AREAS COVERED: An overview of the key advancements in LSF methodology development from 2019 to 2022 and their applicability to drug discovery is provided. In addition, several examples from both academia and industry where LSF methodologies have been applied by medicinal chemists to their drug discovery programs are presented. EXPERT OPINION: Utilization of LSF by medicinal chemists is on the rise, both in academia and in industry. The maturation of the LSF field to produce methodologies bearing increased regioselectivity, scope, and functional group tolerance is envisaged to narrow the gap between methodology development and medicinal chemistry research. The authors predict that the sheer versatility of these techniques in facilitating challenging chemical transformations of bioactive molecules will continue to increase the efficiency of the drug discovery process.