Creating lasting bonds for the benefit of patients

Science Of molecular bonds.

Creating lasting bonds for the benefit of patients Covalency in drug discovery is not new. History shows us that this mode of action can be successful, but only recently have medicinal chemists been able to proactively harness and design covalent drug molecules that permanently and irreversibly modify their target protein. Recent breakthroughs for this class of drugs herald a sea change for the development of medicines that can deliver safe and efficacious drugs with immense benefits to the patient. Text by Goran Mijuk, illustrations by Ikonaut.

Small-molecule drugs are designed to fit into a pocket on disease-causing proteins, thereby disrupting their function and so tempering or stopping a disease.

The better a molecule fits into its target pocket the better its safety profile.

This discovery and design cycle of a successful molecule can take years, with researchers optimizing the shape of the molecule as well as its ability to be dosed in the desired fashion – allowing the prospective drug to be tested in the clinic and show beneficial effects in disease settings.

Today, researchers work intensively with modelers, who can adapt and test molecules in silico to help the accuracy of the design and speed up an otherwise empirical process.

Most small-molecule drugs associate with their disease-causing protein but dissociate and re-bind dynamically and continually: It is only when bound that they can be pharmacologically effective.

Once the drug dissociates, it can be metabolized or excreted, meaning that the patients need to take a new dose and the disease under control.

Irreversible covalent drugs, on the other hand, are different. After recognizing and binding to their protein target, they undergo a second step and quickly create a permanent bond with the disease-causing protein. This means once the drug is bound it cannot leave the body. As a result, the covalent drug can permanently retard the disease-causing function of the target protein.

Such covalent drugs offer the potential to extend their pharmacological action (a pharmacodynamic effect) beyond their pharmacokinetic profile (the time during which detectable drug circulates in the body). This phenomenon would allow for less frequent dosing and enable the patients to use smaller amounts of the drug to control their disease.

Despite this clear advantage, covalency in drug design has been of concern due to the same feature that drives their advantage – the irreversible bonds that are formed must be specific or they can be very dangerous

Historically, covalent drugs were discovered by chance or researchers did not know the drug activity was driven by this mode of action and via this mechanism. Many antibiotics fall in this category, as does aspirin.

More recently some drugs that are now known to be covalent were identified, tested, and developed, without initially understanding their full mechanisms. It was only later discovered that these drugs are “activated” after having been dosed in the patient. Again, these discoveries were largely the result of serendipity within the research community.

Advances within the last decade or so in drug discovery, in design, in understanding the target binding sites on disease-causing proteins and in other parallel technologies have converged and resulted in new strategies being considered to treat specific diseases. These advances have also allowed researchers to mitigate the concerns that these irreversible drugs could have harmful effects by engaging with the wrong target proteins – these can now be managed and determined throughout the discovery process.

The disease-causing protein-covalent drug complex is eventually removed from the body through natural processes, and the target protein is resynthesized for the process to start again.

In the early 2000s, the first covalent drugs were intentionally and prospectively designed to treat cancer.

In its research, Novartis uses this mode of action across a wide range of protein targets and classes, both in oncology and non-oncology indications, creating molecules that are highly specific and bind only to the intended target, creating highly specific ligands that can be advanced into the clinic for the benefit of patients at large.