I have ran three long term pathfinder games off of E with my tabletop group. I have also tried my hand at running a 3.5 game on E. I took over for another GM and the power level was a bit over the top. Although, this was before I had Heroes Lab or any encounter builders. I think even a high level online game would be manageable with heroes lab. Regarding setting, I suggest a homebrew Dark Fantasy setting; we could go for a high magic dark fantasy setting like Dragon Age or a low magic setting like George R.R. Martin's A Song of Ice and Fire/Game of Thrones.
In terms of content, I am fine with NC and some extreme elements, e.g. dragons, demons, angels, minotaurs, orcs, goblins, werewolves, etc. Although, I don't do intimate/smutty scenes with male players. Women with male genitalia and furries are also reds although nearly everything else is negotiable. Regarding the crunch, I usually let my players roll their ability scores via the 4d6 method and start them off at level 1, or level 4-5 if they are playing experienced adventurers in shorter campaigns. We could go with either character generation route in this game.