Motivated by the ongoing COVID-19 pandemic, I am wondering how established density functional theory (DFT) is as a tool/technique in drug design.

Drug molecules come in a wide range of sizes from small molecules (e.g. aspirin) to proteins (biologics) that have complicated intramolecular and intermolecular interactions in a physiological environment, which is often highly concentrated. Is DFT a commonly used tool/technique in drug design? Or is DFT too expensive and inaccurate for us to perform first-principles prediction of drug properties?

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    $\begingroup$ I think DFT is the best tool for drug design if it's not the only one at least, as far as I know. See for example the well established DFT software Schrodinger that is specially designed for drug discovery: schrodinger.com/drug-discovery $\endgroup$ May 5, 2020 at 19:06
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    $\begingroup$ playing the devils advocate a little, I disagree that DFT is used very much in pharma. most pharma are looking for the interaction of drugs with a particular enzyme. For these purposes docking and molecular mechanics are of more value than ab initio results. DFT however, can be useful for helping to guide the synthesis, but again the synthesis of a drug is just one aspect and DFT mechanistic insight on synthesis is not always or hardly ever required. $\endgroup$
    – Cody Aldaz
    May 6, 2020 at 0:04
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    $\begingroup$ And while we're playing devil's advocates, don't forget about the reemerging field of semi-empirics. $\endgroup$ May 7, 2020 at 18:04

1 Answer 1


There are two parameters that are important in such a question: the number of molecules and the size of the systems.

There are some approach used to test a molecule. One is using databases with thousand of molecules. One example of such database is Zinc that have 230M 3D structures that can be downloaded and freely used. The other approach is the combinatorial chemistry. One technique is the de novo design. Using this technique against one target, you can generate more than 2.5M molecules.

As many drugs act inhibiting a protein, a single system will have thousand of atoms.

With all the above in mind, for example, if you want to test molecules against one of the proteins related to COVID-19, you will be dealing with thousand of molecules, which means thousand/million of atoms.

Such huge system are intractable using DFT (even with approaches like Fragment Molecular Orbitals).

So, the solution is to use simple methods like Molecular Mechanics and Molecular Dynamics that use forcefields making the calculations faster.


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