With IF you find out what the exact specs of the simulated plane are...
Let’s just say your plane specs claim:
6000Nmls range
400kts cruise
40000ft cruise alt
You find you only get 4000Nmls
So you can try:
250kts
30000ft
Try less load, shallower climbs, slower climb rates, and so on.
Or in IF you could set the Range Parameter to 4000Nmls and leave it at 400/40000
The route is shortest possible path, same as ATC guides you if there were no other planes.
When you get to your destination and get vectored about, you spend longer in the air and use up precious fuel very quickly, compared to cruising. Add this time to the reserve fuel time.