The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

Abstract

All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increasingly complex targets. This Review article sets out to give a concise appraisal of this symbiotic relationship between organic chemistry and drug discovery, along with a discussion of the design concepts and highlighting key milestones along the journey. In particular, criteria for a high‐quality compound library design enabling efficient virtual navigation of chemical space, as well as rise and fall of concepts for its synthetic exploration (such as combinatorial chemistry; diversity‐, biology‐, lead‐, or fragment‐oriented syntheses; and DNA‐encoded libraries) are critically surveyed.

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds

“…They are also more sp 3 enriched. All these features are in line with recent trends in drug discovery (good or bad) related to increased molecular complexity of new drug molecules ( Grygorenko et al., 2020 ). On the contrary, the average values of total polar surface area, rotatable bond and hydrogen bond acceptor counts for the library members are more or less in line with those of the known drugs.…”

“…Over the last decades, it was stressed out that physico-chemical properties of the compounds are important to drug discovery since they have a critical impact on the attrition rate of drug candidates ( Grygorenko et al., 2020 ). It is therefore important to understand the capabilities of the generated chemical space in terms of providing the so-called drug-like or lead-like compounds ( Nadin et al., 2012 ).…”

Is it time for biocatalysis in fragment-based drug discovery?

“…10 It has been noted that molecules at the limit of the Ro5 space are not always ideal drug candidates, and screening libraries generated by highthroughput screening (HTS) in the 1990s were not structurally diverse. 11 Diversity-oriented synthesis (DOS) was developed to focus on creating structural diversity in compound libraries in Jeremy Ramsden obtained an MChem degree in Chemistry with Medicinal Chemistry from The University of Manchester in 2016, before beginning a PhD at The Manchester Institute of Biotechnology under the supervision of Professor Nicholas Turner. His research is focused on the synthetic application of imine reductase and reductive aminase enzymes with broader interests in enzyme immobilization, ow chemistry and drug discovery.…”

3‐Carboxy‐/3‐Aminobicyclo[1.1.1]pentane‐Derived Sulfonamides and Sulfonyl Fluorides – Advanced Bifunctional Reagents for Organic Synthesis and Drug Discovery

“…The bicyclo[1.1.1]pentyl substituent was proposed as a tert ‐butyl isostere, whereas 1,3‐disubstituted bicyclo[1.1.1]pentane – as a promising replacement for internal alkyne and 1,4‐phenylene motifs , . Such replacements increase three‐dimensionality of the molecules and can improve pharmacokinetic properties such as aqueous solubility, hydrophilicity, and membrane permeability.…”