Predicting where and how drugs will be metabolized is critical in drug design.
Not only does the rate of metabolism dictate the rate of drug clearance, metabolism can also lead to "increased or decreased pharmacological activity, altered pharmacological action, and increased toxicity" (Drug Hunter). Understanding where metabolism will occur and how changes to molecular structure affect metabolism is crucial to developing therapeutics that will succeed in the clinic, not just in vitro.
While in vivo approaches to studying metabolism are the most accurate, they also come with substantial costs and time/material constraints. Computational chemistry can be very helpful in providing quicker and faster estimates of where metabolism might occur as well as providing a simple way to compare potential analogues of a given molecule.
One of the quickest ways to predict metabolism computationally is to use Fukui indices. Fukui indices are a ground-state property which identifies sites of potential reactivity. Electrophilic Fukui indices have been demonstrated to serve as quick, albeit imperfect, estimates of where CYP450 metabolism occurs.
For cases where higher accuracy is required, quantum chemistry can be employed. Bond-dissociation energies are frequently key in predicting sites of C–H oxidation and can be predicted using density-functional theory. Quantum simulations can also be useful in modeling the rates of key reactions involved in substrate metabolism, like reactions of key heme complexes or similar. These transition-state barriers can then be combined with other cheminformatic features to build accurate predictions of site selectivity in metabolism.
Rowan makes it fast and simple to run high-accuracy physics-based simulations to predict potential sites of drug metabolism. Our modern cloud-based platform makes it simple to compute Fukui indices, geometry optimizations, bond-dissociation energy, transition states, and more. Here's what the output of a Fukui calculation looks like:
We let you focus on your science, not your software. All workflows can be submitted, visualized, and analyzed through our browser-based user interface, and Rowan automatically generates publication-quality graphics for each calculation.
