I don't know of a specific algorithm that does this, but covalent inhibitors (by which I assume you mean irreversible inhibitors that form a covalent bond with the protein they bind to) tend to have one of a relatively small number of 'warhead' groups to form the covalent bond with.  So you could reasonably simply set up a SMARTS query to examine the SMILES interpretation of your molecule of interest and look for one of those groups.  Every time you find another such group, just add it to your query.

Hi Carmine, I am "old school" and seeing a computer simulation of a covalent/non covalent  inhibitor does nothing for me.

If the inhibitor is covalent, I would like to see it stick to the protein in an SDS-PAGE gel. If the inhibitor is non-covalent, I would like to see the inhibition kinetics.

Hi William and Steingrimur. Thanks for your advices.

I am investigating the binding mode of a series of novel compounds.

Among the whole series of the compounds, I don't spot evident "warheads" that could block covalently the catalysis. So, we focused the analysis on the two best compounds of this series that were chosen for dilution experiment and showed to behave as reversible inhibitors. Furthermore, the lenght of preincubation time of the enzymatic assays on these compounds excluded time-dependency, so I assume they not display tight-binding.

I performed docking, molecular dynamics and free energy calculation to identify the binding mode of one of these compounds. The computational results converged on the binding site of the crystal structure of known irreversible inhibitors. Therefore, I would try to explain why a binding mode that resemble that of the substrate (and that of the irreversible inhibitors) results in a reversible inhibitor.

Thanks for your suggestions.  

There is nothing surprising about the same enzyme binding site accommodating both irreversible/covalent and reversible/noncovalent inhibitors.

By the way, these are not the only two possibilities. There are also examples of reversible covalent inhibitors and essentially irreversible noncovalent inhibitors.

As for covalent inhibitors, there are different types: mechanism-based and non-mechanism-based.

So there may not be anything that needs explaining.