The science of “smell” and the noble for “hugs:” making “sense?”

David Julius and Ardem Patapoutian were jointly awarded the 2021 Nobel Prize in Physiology and Medicine for their discoveries of receptors for temperature and touch. It was a phenomenal moment for the scientific community, more for the discovery that forms the basic fabric of our everyday life—ever imagined how life would have been without feeling the aroma around? Or even the dangers of accidentally touching a heated object. Dr Julius and Dr Patapoutian, independently discovered key mechanisms of how living organisms sense heat, cold, and touch. The journey started when Dr Julius, at the University of California, San Francisco, used a key ingredient in hot chili peppers to identify a protein in nerve cells that respond to these stimuli. Using capsaicin, the pungent component of chili peppers, he provided fundamental insights into mechanisms of pain. Then using a meticulous cDNA library-based functional screening from sensory neurons to search for the gene(s) that could confer capsaicin sensitivity, Dr Julius identified for the first time a novel ion channel (now called transient receptor potential [TRP] vanilloid 1) belonging to the family of TRP ion channels associated with the pain sensitivity. A painful exercise indeed! While Prof Julius was exploring the oceans and skies to hunt for sensory pain pathways, quite independently, Dr Patapoutian of Scripps Research Institute La Jolla, California, was searching for a similar thing that seemed to bother him equally. How do we sense touches? After all, there are so many emotions packaged in this small five-letter word, touch. The mother’s touch is the first sensation that every single of us always cherishes. Dr Patapoutian research is centered around finding candidate genes in a mechanosensitive cell line that could respond to mechanical stimuli. After a thorough search, the team identified two mechanically-activated ion channels, PIEZO1 and PIEZO2, representing an entirely novel class of mechanical sensors-based ion channels. What is fascinating is the idea that discovery of the smell and touch receptor stretches far beyond just touch and temperature sensations only. Mutations in other TRP channels are involved in neurodegenerative disorders and skeletal dysplasia, while mutations in PIEZO channels help control critical functions such as respiration and blood pressure regulation. So now, the mysterious world surrounding us looks more transparent and clearer. The molecular landscape is defined with precision. We now have a chemical entity behind all these emotions and intuition. The warm hug that makes our day is now millions of ions crisscrossing the ion channels. There is a different side to this too. How will the world look if everything is defined as a chemical entity? Won’t we lose the charm? After all, so much within the subtleness remains charmful when wrapped within the veil of ignorance. Knowing too much about something steals the show.

Prodrug Strategies for Critical Drug Developability Issues: Part I

Drug development is a very time, capital, and labor-intensive process. It was anticipated that bringing a novel chemical entity to market would take over a billion dollars and around 14 years [1]. In addition, drug development is characterized by a very high attrition rate both in preclinical and clinical studies. It was reported that only 40% of drug candidates with the most drug-like properties could make their way into clinical trials, and only 10% of these can eventually reach FDA approval [2]. After analyzing the data from seven UK‐based pharmaceutical companies from 1964 through 1985, Prentis et al. found that 39% of failure was attributed to poor pharmacokinetic (PK) profiles in humans, 29% was attributed to a lack of clinical efficacy, 21% was attributed to toxicity and adverse effects, and about 6% was attributed to commercial limitations [3]. When a drug candidate is identified with one of these issues (except the commercial limitations), normally, a new round of structureactivity or structure-property relationship (SAR/SPR) studies is carried out to generate a new chemical entity with improved profiles, and in most cases, such a process is time and labor-intensive. Alternatively, prodrug strategy can be leveraged to efficiently address associated drug developability issues without making enormous derivatives. Prodrug strategy has been demonstrated to be very successful and fruitful in drug development, with around 20% of approved drugs from 2008 through 2020 being clarified as prodrugs [4]. In recent years, prodrug strategy has also been leveraged to address the delivery issues associated with gasotransmitters, including NO, H2S, CO as well as SO2 [5-8]. In this thematic issue, six excellent reviews were included, focusing on varied prodrug strategies in addressing different drug developability issues associated with anticancer drugs, central nervous system (CNS) drugs, and gasotransmitters....

Chiral Polythiophenes: Part I: Syntheses of Monomeric Precursors

The purpose of this mini-review is to comprehensively present the synthetic approaches used for the preparation of non-racemic mono- and multi-substituted thiophenes, which, in turn, can be applied as precursors for the synthesis of chiral polythiophenes isolated as a single chemical entity or having supramolecular thin-layer architectures.

NLM-Chem, a new resource for chemical entity recognition in PubMed full text literature

Automatically identifying chemical and drug names in scientific publications advances information access for this important class of entities in a variety of biomedical disciplines by enabling improved retrieval and linkage to related concepts. While current methods for tagging chemical entities were developed for the article title and abstract, their performance in the full article text is substantially lower. However, the full text frequently contains more detailed chemical information, such as the properties of chemical compounds, their biological effects and interactions with diseases, genes and other chemicals. We therefore present the NLM-Chem corpus, a full-text resource to support the development and evaluation of automated chemical entity taggers. The NLM-Chem corpus consists of 150 full-text articles, doubly annotated by ten expert NLM indexers, with ~5000 unique chemical name annotations, mapped to ~2000 MeSH identifiers. We also describe a substantially improved chemical entity tagger, with automated annotations for all of PubMed and PMC freely accessible through the PubTator web-based interface and API. The NLM-Chem corpus is freely available.

Abiotic scaffolds in medicinal chemistry: not a waste of chemical space

It is well established that medicinal chemists should depart from the flat, sp2-dominated nature of traditional drugs and incorporate complexities of bioactive natural products, such as sp3-richness, 3D topology and chirality. There is a gray area, however, in the relevance of newly developed chemical scaffolds that exhibit these complexities but do not correlate to anything observed in nature. This can leave synthetic methodologists searching for structural similarities between their newly developed products and known natural products in search of justification. This article offers a perspective on how these types of complex ‘abiotic' scaffolds can be appreciated purely on the basis of their structural novelty, and identifies the unique advantages arising when a complex chemical entity unrecognized by nature is introduced to biological systems.