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Cambridge MedChem Consulting

Macrocycles in the Protein Data Bank

The Protein Data Bank is an absolutely invaluable resource, the PDB is an archive of 3D structural information of proteins, nucleic acids, and bimolecular complex assemblies. However it is much, much more than a simple archive, the submitted structures are curated and annotated to add information about protein ID, sequence information, organism, ligand details etc. This allows users to interrogate the database in many different ways. The database currently holds 141209 entries, with over 10,000 new entries added every year. The vast majority are X-ray crystal structures but there are now over 12,000 NMR derived structures.

The PDB also contains 25626 chemical components - 24007 as free ligands in 106374 PDB file and you can search via a web interface or download the structures in sdf file format. However browsing through the downloaded file it was apparently that macrocycles were not well represented. A discussion with the extraordinarily helpful Rachel Kramer Green at PDB revealed the issue. Basically any ligand containing more that two amino-acids is treated as a protein not a ligand, there are other rules to deal with modified amino-acids etc. but the bottom line is that the only way to get a comprehensive view of macrocycles in the PDB is to download the entire PDB and programmatically by parsing the entire data set.

First we need to decide what size ring constitutes a macrocycle. asking the "internet" failed to produce a definitive answer.


You can read the results and download the script here.


There is also a page that discusses macrocycles in drug discovery.

There is also an upcoming meeting on Macrocycles, 3rd RSC BMCS Medicinal Chemistry Symposium on Macrocycles. Monday-Tuesday, 8th-9th October 2018, GlaxoSmithKline, Stevenage, UK. Full details are here #BMCS_Macrocycles

The objective of this symposium is to promote scientific interaction between scientists with a shared interest in the field of Macrocycles. This area is responsible for a growing number of therapeutic approaches and development candidates, all of which go ‘beyond the rule-of–five’. As a researcher in this field, come along to hear about the latest advances and also to share in some of the secrets of discovering therapeutic agents which go beyond Lipinski’s rules.