Fragment-based drug design (FBDD) has emerged as a powerful strategy in the discovery and development of new pharmaceuticals. This approach involves the identification and optimization of small chemical fragments, which bind with modest affinity to the biological target of interest. These fragments are then used as starting points to develop more potent and selective drug candidates. FBDD offers several advantages over traditional high-throughput screening (HTS), including the ability to explore chemical space more efficiently and the potential to identify novel binding sites on target proteins.
At its core, FBDD relies on the identification of small, structurally simple molecules, typically with molecular weights less than 300 Da. These fragments are screened against a target of interest to find those that bind with even weak affinity. The key to success in FBDD lies in the use of sensitive biophysical techniques, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance (SPR), which can detect these weak interactions.
Once binding fragments are identified, the next step involves growing, linking, or merging these fragments into larger, more complex molecules. This process aims to increase the potency and specificity of the interaction with the target while optimizing the drug-like properties of the molecule.
(This is just a high-level summary: for a more detailed overview with lots of references, see this review by Empting and co-workers.)
FBDD offers several advantages over traditional HTS methods:
FBDD has led to a number of high-profile successes in recent years, including the discovery of sotorasib, a covalent inhibitor of KRAS G12C.
Quantum chemistry plays a pivotal role in the optimization of fragment hits identified during FBDD. Its computational methods allow for the detailed characterization of the electronic and structural features of the fragment-target interaction, providing insights that are invaluable for the rational design of more potent and selective drug candidates.
Quantum chemical calculations can be used to estimate the binding energies of fragments to their targets, offering a more nuanced understanding of the interaction than what might be apparent from experimental data alone. These calculations can also identify key functional groups within the fragment that contribute to binding, guiding the modification of these groups to enhance affinity and specificity. Recently, Vasile and Roos investigated this approach in the context of discovering novel metalloenzyme inhibitors; since metalloenzymes are often handled poorly by classical forcefields, quantum chemical methods are an appealing alternative.
Quantum chemistry can also predict important drug-like properties of fragment-derived molecules, such as solubility, permeability, and metabolic stability. This information can be used to prioritize which fragments to pursue based on their potential as viable drug candidates.
Despite its advantages, quantum chemistry is limited by its computational intensity, particularly when dealing with large biomolecular complexes typical in FBDD. This is where platforms like Rowan come into play. Rowan's cloud-based platform leverages modern computational methods, including faster machine learning-based quantum chemical methods, to significantly reduce the time and resources required for these calculations. By doing so, Rowan enables the rapid optimization of fragment hits, making quantum chemical insights more accessible and actionable during the drug design process.
Fragment-based drug design represents a strategic shift in how pharmaceuticals are discovered, offering a more efficient and targeted approach to identifying novel drug candidates. The integration of quantum chemistry into FBDD workflows, especially when facilitated by platforms like Rowan, enhances the rational design of new drugs by providing deep insights into fragment-target interactions and drug-like properties. As the field continues to evolve, the synergy between FBDD and quantum chemistry promises to accelerate the discovery of new therapeutics.
For researchers and pharmaceutical companies looking to explore the benefits of FBDD and quantum chemistry, Rowan offers a powerful suite of tools designed to streamline the drug discovery process. Create an account on Rowan today and start leveraging the power of quantum chemistry in your drug design projects.