From the Lab ofDr. Nir London
Weizmann Institute of Science
Computational protocols for thedesign of next generation chemical tools.
Covalent irreversible inhibitors, andprotein degraders (PROTACs) are two emerging fields that are growing rapidlyover the past decade. Such molecular modulators have several advantagescompared to traditional drugs. Irreversible inhibitors have a longer residencetime, time dependent inhibition, and improved potency. PROTACs are alsoeffective at lower concentrations, due to their catalytic effect, and theirrecyclable nature. Yet, both field suffer from lack of computational tools forthe rational design of compounds. We developed computational protocols forthese two domains that are built on simple geometrically oriented schemes whichleverage the specific nature of the problems at hand.
Inthe field of covalent and irreversible inhibitors, I will present – Covalentizer, apipeline for turning reversible non-covalent inhibitors into covalent ones,based on a crystal structure of the molecule bound to its target protein. Apublic database with predictions against the entire protein data bank (PDB),including over 1500 covalentized structureswas made available at https://covalentizer.weizmann.ac.il/. Wetested the method retrospectively and successfully recapitulated known covalentkinase inhibitors, given only their reversible recognition elements.Furthermore, selected candidates were synthesized and tested, and a few novelcovalent kinase inhibitors, as well as an inhibitor for the SARS-CoV-2 mainprotease were discovered .
Inthe field of PROTACs, I shall present the ProsettaC protocol,which predicts ternary complexes between the degradation target, the E3 ligaseand the PROTAC. This is achieved by alternating between the sampling of theprotein-protein interaction space, and the PROTAC molecular conformationalspace. It was used to recapitulate crystal structures with atomic accuracy, aswell as prospectively predict a new ternary complex with high confidence .The method is available at https://prosettac.weizmann.ac.il/. Ina second project, by a group effort, we created a public database of PROTACs,which will be based on contributions and reviews from members of the entirePROTAC community. It is available at https://protacdb.weizmann.ac.il/.
Thesetools, combined with our efforts to make them publicly available, should enablebroad access to new and improved chemical probes.