More than a decade ago, we have launched an in-house project on the generation of a virtual compound database based on the experimentally validated synthetic accessibility (the so-called REAL Database, where REAL is for REadily AccessibLe). Further extension of this concept led to the development of REAL Space, a searchable chemical space that is not typically stored as an enumerated database but generated upon query through chemoinformatics software. Until now the largest REAL Space has comprised 15.5 billion make-on-demand molecules and is currently the largest offer of commercially available compounds. Recently, utility of the REAL methodology was confirmed by discovery of highly potent AmpC β-lactamase inhibitors, D4 dopamine receptor ligands, and Kelch-like ECH-associated protein 1 (KEAP1) inhibitors published in Nature (see Nature 2019, 566, 224–229 and Nature 2020, 580, 663–668).
A diastereoselective approach to cis- and trans-1,3-disubstituted bicyclo[2.1.0]pentanes (housanes) was recently reported by our chemists in The Journal of Organic Chemistry. The article included preparation of 35 derivatives on up to 100 g scale. Moreover, pKa’s and conformational features of selected examples of housanes (e.g. GABA analogues) were also studied and compared to that of the corresponding 1,3-disubstituted cyclopentanes. For an extended list of novel housanes check the Enamine Store page.
In a recent JOC paper, Enamine chemists reported a comprehensive study of regioselective [3 + 2] cycloaddition reactions – an efficient approach towards 3,5-disubstituted isoxazole building blocks bearing mono-, di- or trifluoromethyl substituents. More than 100 derivatives were obtained on up to 130 g scale, and multigram quantities of representative examples are available from EnamineStore at the isoxazole library.
Enamine’s EurJOC paper on the scalable and regioselective preparation of all isomeric (cyclo)alkyl piperidines and the corresponding amino alcohols was featured on the cover of the issue. The multigram quantities of these derivatives are available from EnamineStore at the piperidine library
Recent Enamine’s paper disclosed novel heteroaryl difluoroacetates and the corresponding carboxylic acids, amides, nitriles and alcohols as promising building block in drug design. Known literature example of metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitor 1 led to the the corresponding 2,2-difluoro-2-pyridin-2-yl derivative 2, which is not prone to metabolic oxidation at the α-methylene group next to the aromatic moiety.
The review mentioned in the title was published in Chemistry – A European journal and emerged from a collaboration of scientists from Enamine Ltd. (including myself) and Duncan Judd from Awridian Ltd. Despite some “symbiotic” hype in the title (as it was pointed out by one of the reviewers), the paper provides a comprehensive overview of concepts which appeared at the edge of these disciplines recently. Initially, we have aimed at tutorial review that might help synthetic chemists to become familiar with state-of-the-art in the field. Thus, genesis of concepts like “…-oriented” syntheses (DOS, LOS, BIOS, FOS, DTS), as well as related “abbreviated” strategies (BBs, FBDD, DEL, REAL) has been discussed, together with recent advances focusing mainly on chemical aspects.
However, the paper exceeded the initial “tutorial” goal, and in my opinion, it might be of interest not only to beginners in the field, but also to highly qualified specialists in medicinal chemistry and related sciences. Although we attempted to be as neutral as possible, one might feel that we advocated for the compound selection models taking into account physico-chemical properties of the compounds, and hence concepts like lead-oriented-synthesis (LOS). Despite recent criticism and numerous successful exceptions, we believe that if used properly, such strategies might be step at the right direction for early drug discovery. In particular, LOS-like concepts seem to be dominating for building blocks, and majority of the Enamine’s building block collection have been designed by the corresponding criteria such as “the smaller, the better”.
The title picture (which was also used as a frontispiece for the paper) shows one of the most beautiful examples of symbiosis found in Nature – a hummingbird pollinating an ornithophilous flower. These two families co-evolved together, changing their features (i.e. the bill shape of the bird, as well as color spectrum and nectar composition of the plant) to get maximum benefit from their interaction. This is a good illustration of the main concept of the paper: similar symbiotic relationship between synthetic organic chemistry and early drug discovery exists.
Things like gene editing, stem cells, immunotherapies and new types of biologics are now mega-trends in the pharmaceutical industry, widely covered in media, and I guess there is little doubt that biology is the next big thing in medicine. However, in this post I would like to outline several promising areas in small molecule drug discovery, suggesting a lot of untapped potential and investment prospects in this more “traditional” pharmaceutical research space.
1.Targeting ribonucleic acid (RNA)
The majority of existing marketed drugs out there are designed to somehow modulate proteins in the body, thereby disrupting a disease progression. However, going one step back and trying to disrupt a pathological process earlier -- right before a protein is actually made in the body -- seems a powerful concept. This can be achieved by influencing ribonucleic acid (RNA), a central actor molecule in the process of gene expression -- the one leading to the formation of proteins as instructed by the human genome.
Enamine has the world’s largest catalogue of building blocks which is monthly enriched with ca. 2,000 newly designed and synthesized compounds. Most of these compounds have been previously unknown and may already provide elegant solutions to your today’s challenges.
Being the global leader in supplying state-of-the-art chemical products for drug discovery (building blocks and screening compounds), Enamine also created a sophisticated ecommerce integration layer, allowing for a seamless eProcurment process to be enabled between buyers and vendors.
(This article originally appeared at Sciencetrends.com)
Modern drug discovery relies heavily on the ability of chemists to produce good starting points for producing high-quality lead compounds. Several concepts were established in the last two decades to aim synthetic organic chemistry onto the proper areas of chemical space, in particular, the so-called lead-oriented approach which describes paradigm shift towards low-molecular-weight, relatively hydrophilic, conformationally restricted, sp3-enriched structures.
(This post originally appeared on Forbes)
Pioneered by expensive and cumbersome legacy electronic data interchange (EDI) systems, the B2B e-commerce market has been evolving, showing a staggering growth rate with a projected volume of $1.1 trillion in the U.S. alone and $6.7 trillion globally by 2020.
(This post originally appeared on LinkedIn)
Notoriously toxic, covalent inhibitors have been nearly excluded from major drug discovery programs in the not so distant past. Ironically, a great amount of the important drugs exploit covalent inhibition as their mechanism of action (MOA). The view on covalent inhibitors is shifting towards a wider consideration, however, inspired by recent successes with EGFR inhibitors for treating cancer and many other promising examples. A recent publication in Nature provides a chemical proteomic platform for the global and quantitative analysis of lysine residues in native biological systems, offering further insights and ideas in this area.
(This article originally appeared at Forbes.com)
Artificial intelligence (AI) has become a hot topic in the area of life sciences lately. With a growing number of groundbreaking AI use cases in other hi-tech industries -- ranging from self-driving cars to speech and image recognition tools to personal assistants (you know Siri, don’t you?) -- players in the biopharmaceutical industry are looking toward AI to speed up drug discovery, cut R&D costs, decrease failure rates in drug trials and eventually create better medicines.
Scientists estimated that the human genome encodes above 20,000 different proteins in our body. However, available public databases contain records of known ligands for only about 10% of all proteins. The rest of proteins remains either not yet properly explored, or is labelled “undruggable”.