Restrict shipping to PO Box? I don't ship to Po box
Shipping freight option? Some products I need to ship freight and disable shipping to other country's as I can only ship these items continental USA only.
I don't recall seeing PO box restriction, all other shipping options are available, they have made it unnecessarily complicated but they are doable. So if you are not planning to use multivendor you will have to worry about complicated setup one time which in my opinion is not a deal breaker.
Freight we do with various APIs like Estes and YRC - this depends heavily on what you are using to calculate freight rates (if real time) and what parameters. E.g. Pallet limits & items per pallet.
Restricting by country is trickier. You cannot prevent them from starting checkout, so you should add text that tells them this product is not available.
Then you use localization to restrict the product by Shipping Location. You just add a friendly message when they attempt to pull shipping rates and let them know they have to remove the product to checkout (assuming you have other products they can order that are not restricted).
Items 1 & 2 are custom .. but not difficult. We're always available to consult.