Well, if by challenging you mean more complicated than most other parcels which have fewer alternatives, then sure. The thing is, that combo zoning isn't even the most common way such projects get built. As evidenced by the point that most existing mixed use projects (in my region, anyway) weren't built on multi-zoned parcels.
Zoning itself isn't the only element involved. Let's say I have a parcel zoned for light commercial or office/professional or whatnot but it's got a secondary location. If the zoning regs for those sites also allow mixed use that might be the most profitable way to develop those sites, which in turn would make those sites directly comparable to each other and to the subject despite the different zoning. Shape of the lot comes into play, too. For a narrow/deep parcel the rear half doesn't have as much utility to a commercial use as the front half, so in that situation adding a residential use or a service use might be a more profitable use of that portion of the site.
Drive through these business districts of these small towns located out and away from the huge metro areas and look at all the wierdo one-off properties that pop up on Main Street and in the transitional zones paralleling Main Street. Those all get appraised, too. If your day job included the wide cross section of property types and combos you'd eventually become acclimated to those problems. It's no different than appraising an SFR in a neighborhood you're not familiar with - the process isn't actually different, it's just "more".