As a guitarist I love using a real valve amp that's heating the room, in a big wooden box that's thrumming with the vibration of nasty breaking up guitar speakers that rattle the valves.
But yes, when I use amp sims because I know what I like in terms of my rig I'll usually start with a blank preset then add only the exact things I know I want - I pretend it's a real setup!
My experience with amps is that some need tightening up and some don't. A Mesa Dual Rec has massive low end and quite unfocussed upper mids, a TS-9 or SD-1 is the perfect antidote and the combination just works. Same with a clean fender - scooped amp sound takes a mid humped pedal nicely. On the other hand, my Mesa Stiletto combo has a very tight low end and very focussed mids, to the point that hitting it with a tubescreamer does nothing other than make it sound overcompressed and chesty. When I gigged an AC30 I had to be careful with TS style pedals to avoid a shouty, harsh tone.
Same principle with modelled amps, I'd imagine.I'd just listen to the amp you reckon you want to use, see how close you can get the tone just with the amp controls, then add a pedal sim if you think it'll get you there.