Covalent inhibitors

Emerging trends: Covalent inhibitors

Over recent years, targeted covalent inhibitors (TCI) have gained popularity as a good alternative to small molecule therapies due to their ability to target shallow binding sites, improved efficiency and hence the possibility of lowering the dose. It is no wonder that the number of covalent drug candidates has skyrocketed in the last decade, with over 50 compounds currently on the market!

Naturally, this evolution is going hand in hand with the development of new computational methods, especially covalent docking tools, such as Schrödinger’s CovDock, MOE and AutoDock, just to name a few. As a company, we like to stay on top of current developments… which is why a few months ago, together with the Electronic and Atomic Protein Modeling group at the Barcelona Supercomputing Center, we started the development of a covalent docking protocol in PELE.

In order to predict the conformation of the bound covalent complex, we are combining a specific protocol for covalent ligands along with our well-established backbone perturbation and side-chain sampling algorithms. As a result, we can explore different conformations of covalent ligands and select the most promising poses in a matter of hours while taking protein flexibility into account with high precision. We are hoping this algorithm will open the doors to a wide world of possibilities such as linking it to fragPELE to grow custom fragments onto any side chain, as well as refine docking poses obtained with other software packages, e.g. CovDock.

Of course, this is merely a small taste of what is coming, so stay tuned for more updates!

RSC Med. Chem., 2020, 11, 876-884

J. Chem. Inf. Model. 2018, 58, 7, 1441–1458