When opening a journal focused on medicinal chemistry or drug development from 10, 20, or 50 years ago, one will find familiar themes. One is the steady dominance of enzymes and receptors as targets for agents acting across the antagonist/partial agonist/agonist continuum. In addition, those agents would most likely have classical small, drug-like molecular structures or be derived from a natural product heritage. And although the years have seen advances like the addition of biologics, many important therapeutic goals continue to be addressed by small molecules acting through established pathways.
No healthy scientific endeavor stays still, however, and exciting new approaches are being pursued throughout every avenue of drug discovery. In this Virtual Special Issue (VSI), we seek to highlight papers that feature these new modalities and, in so doing, provide a spotlight on the cutting edge of contemporary medicinal chemistry. These papers were mostly submitted through the normal procedure and reflect all article types of the host journals for this VSI. We have sought to be broad-minded in the identification of these papers, although several themes do reveal themselves throughout the portfolio. For example, protein degradation has very quickly become a go-to technique across therapeutic areas, and synthetic molecules, like macrocycles, in addition to oligopeptides, that split the molecular mass difference between classical drugs and the biologics class, are receiving increased attention.
Besides classical biologics, i.e., polypeptides, various further polymeric drugs, e.g., aptamers consisting of single-stranded nucleic acids, and polymeric polyphenols (tannic acids), are subjects of publications in this VSI. Several articles focus on conjugates of small molecules to alter pharmacokinetic properties and to modulate pharmacological effects.
Finally, multi-target drugs are described, that prove the recent paradigm change from drugs for single targets to polypharmacology. Articles published in this VSI also describe molecules interacting with new drug targets, and with novel mechanisms of action.
Across all of these new modalities, the value of mid-size (MW 600–800) and large molecules (MW 900+), so-called beyond rule-of-5 compounds, is clear. These atypical molecules demonstrate excellent physiochemical and DMPK (drug metabolism and pharmacokinetics) properties, affording oral bioavailability and central nervous system penetration. Have we been too restrictive on ourselves, and operating/designing within unnecessary limitations the past 20 years? Only time and new drug applications will tell.
We’re not time travelers and therefore unable to predict what medicinal chemistry will look like in the future, but if past experience is any guide, these new modalities stand a good chance of being viewed as old standards 20 years from now.
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.