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Cambridge MedChem Consulting

A review of Bioisosteres in Medicinal Chemistry

When I look at the weblogs of the Drug Discovery Resources section of my website it is clear that two sections are of particular interest, Fragment-Based screening attracts a steady stream of readers and the other area that is very popular is the section on Bioisosteres. The former because it is an increasingly popular, effective and low cost entry point into screening for leads, the latter presumably because it provides a great way to generate ideas of what one might do next.

I’m not aware of a book dedicated solely to Bioisosteres so I was delighted to hear about a new book in the area Bioisosteres in Medicinal Chemistry edited by Nathan Brown.

Having had time to read through the book I thought I’d post my thoughts.

A bioisostere is a molecule resulting from the exchange of an atom or of a group of atoms with an alternative, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new molecule with similar biological properties to the parent compound, but perhaps with improved physicochemical or ADME properties. Whilst the experienced Medicinal Chemist will have a toolbox of such replacements, this book is an excellent resource that provides a logical framework to this area of drug discovery that will be useful to all.

The book is organised into four section, the first deals with classical replacements, the second the discovery of bioisosteres based on database mining, the third section deals with physicochemical properties and shape, the final section includes the application of bioisosterism in a drug discovery project.

The book starts by giving a short history of bioisosteres and several examples of the attempts to define what is exactly meant by a bioisostere, it then quickly moves onto description of the development of many of the classical bioisosteres, giving plenty of examples and references. The influence of the bioisostere on ADME properties is also introduced again with plenty of key examples. The second section starts by describing the evolution of the Bioster database that has been created by abstracting examples from the Medicinal Chemistry literature. There is also a description of how it might be used as a source of bioisosteric replacements. In contrast mining the Cambridge Structural Database has the potential to identify unexpected replacements based on the arrangement of potential non-bonding interactions. As mentioned agove one of the key drivers for looking at bioisosteres is to improve ADME properties, and mining a large database of metabolic stability data has allowed the identification of transformations that are more likely to improve stability. The third section deals with physicochemical properties, molecular topology and shape, describing in some detail the in silico techniques that can be used to scaffold hop to identify novel frameworks. The final section describes the Drug Guru project, and the use of the molecular field based screening in a NPY-Y5 project.

In summary the book is an excellent starting point for new medicinal chemists and a useful resource for more experienced scientists to dip into to generate ideas. in summary every chemist involved in drug discovery would benefit from access to this book.