How to effectively use chemical space to help develop new drugs?

The chemical space, according to the structural characteristics of organic small molecule compounds, uses a specific algorithm to describe the collection of small organic compounds in the form of mathematical figures. The chemical space in the broad sense is an unusually large collection of molecules, which is all-inclusive, even larger than the organic compounds that have been prepared by synthetic chemistry. This generalized chemical space does not have much practical significance for the development of new drugs. Therefore, a variety of subspace databases with special significance have emerged. As Jean-Louis Reymond compares the characteristics and use of the current mainstream chemical space database in the article The Chemical Space Project, the GDB-17 database covers the largest number of drug-like molecules and has reached 166.4 billion. Of course, all kinds of databases have their own characteristics. Although the basis of the investigation, the algorithm and the direction of the establishment are different, they still play a good guiding role for the transformation of drug molecules and the deeper chemical space expansion.

DNA coding compound library screening results (2014.3.1-2016.6.30)

In addition to GSK2256294, which has completed clinical phase I treatment for chronic obstructive pulmonary disease, there are still many excellent compounds from the DEL technology. The active compounds screened based on the DEL technology disclosed during the period from 2014.3.1 to 2016.6.30 are as follows.

DNA-encoded compound libraries cover a wider range of chemical spaces. So what is the current chemical space of the DNA coding compound library? How much chemical space does the molecular structure type of the DNA-encoding compound library cover? What kind of distribution does the physical and chemical properties of the molecule show? Perhaps these are all things that everyone is eager to understand.

The authors of the Chemical Space of DNA-Encoded Libraries, Raphael M. Franzini and Cassie Randolph, have summarized the molecular weight (MW) of the active compounds that have been actively screened from the DNA-coding compound library by a large amount of experimental data. The approximate distribution of physicochemical properties such as hydrophobic parameters (ClogP), and related studies on DNA-compatible chemical reactions (DEC) used in these molecules. Oliv Eidam and Alexander L. Satz also conducted a study on the chemical space of DNA-encoded compound libraries based on the Small Molecule Compound Activity Screening Database (ChEMBL) in "Analysis of the productivity of DNA encoded libraries" and obtained similar results.

It can be easily seen from many scientific research results that the DNA coded library can cover a wider chemical space, which is very conducive to the expansion of the chemical space of drug-like molecules. But there are also some problems that need improvement. For example, compared to other physicochemical properties of the compound, the problem of large molecular weight is prominent in various properties of the DNA-encoded compound. As the dimensions of the DNA-encoded compound library increase, the molecular weight also increases significantly. However, the article also pointed out that even so, the molecular weight of most DNA-encoding compounds is still lower than that of early combinatorial chemistry, and other physicochemical properties are distributed in a relatively good range.

In order to better expand the chemical space of DNA-encoding compound libraries, establish a library of DNA-encoded compounds with better compound properties, increase the number of active compounds, and improve the properties of the target compounds, it is impossible to simply increase the size of the DNA-coded library. Increasing the number of DNA-encoding compounds requires radically increasing the diversity of compound library molecules, covering larger and more medicinal chemical spaces; developing more new DNA-compatible chemical reaction types (DEC) to make compounds more structurally compact while effectively reducing molecular weight.

Even if faced with many challenges, as Robert finally stated in the article, the continuous investment in DNA encoded libraries will continue to deepen the application of this technology in broadening the molecular space of drug-like molecules.

BOC Sciences is a traditionally chemical supplier, and starting last year, it has become a highly proved provider of comprehensive drug discovery services, which includes various screening libraries like Fragment Library and Custom Libraries as well as services like Hit to Lead, Lead Optimization, Chemical Resynthesis, drug testing service and more.

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This article is provided by BOC Sciences.