Covalent Inhibitors

Covalent inhibitors are small-molecule therapeutics that operate by forming a covalent bond with their target. Typically, covalent inhibitors contain an electrophilic warhead that reacts with a nucleophilic residue on the target protein, like cysteine or lysine. They possess several advantages over conventional non-covalent inhibitors, including greater potency, decreased dosing frequency and improved compliance, and the ability to target shallow binding sights. As a result covalent inhibitors have dramatically increased on popularity in recent decades; today about 30% of small-molecule drugs operate through a covalent inhibition mechanism.

Challenges in Developing Covalent Inhibitors

Despite the advantages mentioned above, covalent inhibitors also come with a unique set of challenges. Administering a reactive covalent warhead has the potential to cause dramatic off-target toxicity or immunogenicity as the warhead can react indiscriminately with other cellular residues. Successful development of a targeted covalent inhibitor requires precise control of reactivity and selectivity: the drug must be reactive enough to react with the desired target when complexed without being so reactive that it reacts with other nucleophiles.

Accordingly, rational design and modulation of the covalent warhead is crucial. Unfortunately, selecting a suitable covalent warhead and fine-tuning its electrophilicity through conformational and stereoelectronic factors is difficult to model with conventional molecular mechanics-based computations as these topology-based methods are largely incapable of describing changes in bonding. Quantum mechanics-based methods are capable of modeling the necessary reactive processes with high fidelity, but they require expert training and lots of computer time, often making them impractical for fast-moving drug design teams.

Accelerating the Design of Covalent Inhibitors with Computation

Rowan makes it possible to use cutting-edge computational tools in the design of covalent inhibitors.

Rowan's global electrophilicity workflow is purpose-built for designing covalent inhibitors. Global electrophilicity calculations quantify the propensity of a given fragment to react with a covalent nucleophile (like cysteine), and run many times faster than the corresponding transition-state calculation, making it possible to assess potential warheads in just seconds. This workflow even works across disparate inhibitor structures, so researchers can quickly assess the effect of scaffold hops or warhead changes before conducting time-consuming experiments on leading candidates.

For cases in which maximum accuracy is desired, Rowan allows for transition-state optimizations to be carried at numerous levels of theory, including modern machine learning-based methods and high-accuracy density functionals developed in the last few years. All calculations can be submitted, visualized, and analyzed through our browser-based user interface, making it simple to run high-accuracy calculations for your system.

If regioselectivity is in question, Rowan's Fukui index workflow allows users to quickly quantify potential sites of nucleophilic and electrophilic reactivity.