Elucidating the bioactive conformation of CCR5 Chemokine Receptor inhibitors

There are still many projects which do not have a relevant protein-ligand crystal structure to drive compound design. This includes those targeting GPCRs and Ion Channels as well as those working with phenotypic or whole-organism screens. In such cases, field pharmacophore modeling as implemented in FieldTemplater can help to decipher how and which active compounds interact with a common protein target and which parts of those active molecules are involved in binding, in the absence of any protein information.

FieldTemplater generates a series of conformations that the ligands might adopt at physiological conditions. It analyzes these conformations to find sets that show a high molecular field similarity (and hence have similar shape/binding properties). Where all the ligands with a common activity align well, it is very likely that this is the bioactive conformation.

The case study Elucidating the bioactive conformation of CCR5 Chemokine Receptor inhibitors shows how FieldTemplater, working from just a few 2D structures of known active CCR5 Chemokine Receptor inhibitors, was able to correctly reproduce the bioactive conformation of the CCR5 receptor inhibitor Maraviroc as derived from the 4MBS PDB crystal structure, without making use of the X-ray information about the binding mode of this ligand. Additionally, FieldTemplater indicates the relative alignments and likely bioactive conformations of 3 further CCR5 inhibitors enabling the transfer of SAR between series. The case study gives full experimental details and results and is used in a web clip to show the power of the Cresset Engine Broker to accelerate computationally intensive experiments.

Dr Giovanna Tedesco, Product Manager