As someone who is in airplane engineering, the biggest barrier today to building a new aircraft is regulations. But if we completely ignored regulations, and you were building a mostly aluminum aircraft with analog avionics and the goal was just to get it to fly (nevermind things like designing for fatigue), then no it wouldn't be that difficult conceptually on paper. However, manufacturing would still be the bottleneck, and that is still challenging today (tolerances, QA, technical expertise).
However, if you were designing and building a new aircraft to meet the latest Part 25 regulations for passenger transport, it's almost insurmountable. There's a reason why there are so few aircraft OEMs.
And to go along with it for Part 25, you're pretty much guaranteed to be doing something "thinking outside the box" if you're doing a clean-sheet design, because the current models (737 Max8, A320, etc) are all pretty darned close to their local optima. No one's going to do a clean-sheet design for 5% more pax and 5% less fuel burn, they're just going to riff on something that already has type approval so that a good chunk of the regulatory burden is already mostly taken care of.
However, if you were designing and building a new aircraft to meet the latest Part 25 regulations for passenger transport, it's almost insurmountable. There's a reason why there are so few aircraft OEMs.