Ferruccio Palazzesi Abstract

A fast ab-initio predictor tool for covalent reactivity estimation

Ferruccio Palazzesi¹, Marc Grundl¹, Alexander Pautsch¹, Alexander Weber¹

¹Boehringer Ingelheim Pharma GmbH & Co. KG

In the last decades, the pharmaceutical industry has witnessed the successful resurgence of covalent drugs, thanks to their unique characteristics with respect to conventional non-covalent ligands [1].

One of the key aspects of the optimization process of covalent drugs is the modulation of the reactive functional group, the so-called “warhead”. This electrophilic group can react with specific nucleophilic residues, such as cysteine, lysine or others, and covalently bind to the target protein. Increasing reactivity of the warhead results in faster formation of ligand protein adducts leading to improved potency. At the same time, selectivity and toxicity issues can occur due to none-specific binding of highly reactive compounds. Identifying and tuning reactivity of suitable warheads is therefore fundamental for successfully optimizing covalent inhibitors.

For this reason, researchers developed experimental assays to evaluate and classify the reactivity of covalent warheads [2]. However, time and capacity consuming synthesis and testing of corresponding compounds are required. In this context, a more focused, faster design of covalent binders with reliable computational chemistry methods would be beneficial.
Here, we present the implementation of a general in silico approach able to predict covalent warhead reactivity. This approach, based on ab-initio calculations [3], is extremely fast and does not require any a priori knowledge of the reaction pathways and system transition states.

We believe that this approach will have a strong influence in the design process of covalent drugs, leading to faster identification of safer and more potent compounds.