There's a few that I address, depending on the amp or tone I'm going for, but basically:
Master Volume: For modern high gain tones, you don't want this too high. There's a point where the poweramp starts introducing flubbiness for a lack of a better word. Lower master volume ranges between 0.5 and 1.5 tend to work the best. Just consider that these amps in the real world are insanely loud, so you often won't exceed those master volume settings, which means that is what most people are accustomed to.
Overdrive Pedal: This is a tried and true method with 0-3 on the drive, tone to taste, and 5-10 on the level. You can use the graphic eq in this block to get additional tightness and clarity by using an asymmetrical upside smiley face shape. You're not worried about losing lowend here because can reintroduce post gain stages in the amp via depth knob, or output eq.
Amp Block Output EQ: Use this to regain your lost lowend. Also the 400-500hz range is notorious for honking up your low mids, so I pull a little here if the tone calls for it.
Post Cab PEQ: I'll use this to to rolloff some of the lowend that I reintroduced, as well as additional fine tuning of the 400-500hz range, and maybe some of the upper midrange to get rid of the harsh timbre there.
That's my main tweaks, and works for most cases of what I try to do. There are additonal things you can do with filter blocks before your drive and amp blocks, and multiband compressor, but the above should yield fairly useable tones for what you're trying to achieve.