If exploration is the basic objective, then N-5 is your best bet. It will go through nearly every important city enroute, and you can visit the places that you like. Again, I don't know much about Punjab, but you can visit Kot Diji Fort right after Khairpur. OR if you are willing to make some detours, then when you're done with Karachi, you will have multiple options such as exploring Makran Coastal Highway till Kund Malir or even up to Princess of Hope (which can be managed in a day-tour although it could be quite hectic), another option is to explore Tharparkar and Umerkot (ideally a 2night-3day trip).
For the routes that I mentioned earlier, route 1 (Qazi Ahmed > Hyderabad via N-5) goes through Hala where Shah Abdul Latif Bhitai's shrine is. Not for anything else, but since we have heard so much about the sufi poet, the shrine has a significance--for some people--to visit.
Whereas route 2 (Qazi Ahmed > Hyderabad via N-55) goes near Sehwan which has Laal Shahbaz Qalandar's mazaar as well as the option to visit Manchar Lake and Ranikot Fort. However, please note that you have to back-track a bit in order to go to Sehwan/Manchar as they are on the opposite side to Hyderabad.
Alternatively, you can design your trip in such a way that you use N-5 while coming down, and go through N-55 while going back. This way you will explore both routes and see maximum cities.
If time and other resources aren't an issue, you can design your itinerary in this way (I will only comment on Sindh part).
Revised Route: M1 (Isb) > M2 (Pindi Bhattian) > M4 (Multan) > M5 (Sukkur) > N5 (Khairpur > Tando Masti Khan) > Larkana/Khairpur Road > Mohenjo Daro > N55 (Naseerabad > Hyderabad via Sehwan) > M9 (Karachi)
After crossing Khairpur take a left turn from Tando Masti Khan to visit Kot Diji Fort and then go towards Larkana where you will have a chance to visit Mohenjo Daro. You don't have to go to Larkana for that, you have to change course and visit the ancient site. Re-connect to N-55 at Naseerabad, and now you don't have to back-track for Sehwan. Follow the route till Jamshoro and then connect M-9 at Hyderabad to Karachi. You will have the option to visit Gorakh Hill station near Dadu but that will require a night stay. For that you will have to leave you car either at Wahi Pandi or Johi, and hire a 4x4 from there.
When you are done with Karachi, as I said earlier, you can visit and explore a bit of Balochistan till Kund Malir beach or till Princess of Hope. After that you can design your journey back in the following manner.
N-5 > Karachi to Makli (One of the largest cemetery in the world, as well as one of the most ancient necropolis). Total time will be around 1 hour 45-min, give or take 15-min, depending upon where in Karachi you start your journey. You will be needing about 1.5-2 hours for sight seeing. Another worthwhile attraction is the Shahjahan Mosque in Thatta which is 15-min drive from Makli. Another 30-min to 1 hour is required to see that.
The same road will take you to Mithi (Tharparkar) via Sajawal-Badin in about 3-hours. Another 2-hours are required to reach Nangarparkar. You can either stay at Mithi or a little further away at Islamkot. If you are willing to spend 2-nights there, then my suggestion is to stay for the 1st night at Nagarparkar, which is easily do-able from Karachi enroute Makli/Thatta. The next day, visit Karoonjhar mountains, Jain Temple, Bodhesar Mosque, and Gori Temple, as well as Thar Coal mines. Stay 2nd night either at Islamkot or Mithi (40-min drive from Islamkot to Mithi), then leave for Umerkot (the birth place of Mughal Emperor Akbar) via Naukot (which also has a small fort right at the Naukot-Umerkot road).
From Umerkot, connect to N-5 at Hala via Mirpurkhas and Tando Adam. The remaining route will be the same i.e. N-5 (Hala to Sukkur) > M-5 (Sukkur-Multan Motorway) and so on so forth.
To summarize, you will have the following attractions to decide from.
Kot Digi Fort (near Khairpur)
Mohenjo Daro (near Larkana)
Gorakh Hill (near Dadu, night stay available)
Manchar Lake and Ranikot Fort (near Sehwan, night stay available at Ranikot fort)
Makran Coastal Highway (Balochistan)
Makli/Thatta (day trip from Karachi can be easily done, OR enroute to Tharparkar is do-able)
Tharparkar (Ideally 2-night/3-day)
Umerkot
Hala, near Bhit Shah
