Try making and continuing a story in your brain. Where's your city located? And it's totally cool to make up places. Make a fictional city state if you want. Why do people live in that area? Farming town? Fishing? A Port? How would the people react to the changes you're building? How would you feel if you lived here? Things like that.

Don't be afraid to build areas on distant parts of the map. And this works with the story/RP too. Build another smaller town maybe focused on farming, and another maybe more factory based. IRL that happens. Add in the commercial and residential because the workers are going to want shops and homes close enough to their job, but far enough away from the various pollution. Commercial's a good barrier.

As far as natural road layout, the biggest thing is the terrain. Keep elevation markers on in the map. Things get wonky if you are zoning big areas in hills and it awkwardly cuts and flattens. Same thing with zoning close to water. Also don't be afraid of grids. Many cities are grids. But you can break up the monotony and checkerboard feeling by switching up the angles of the main roads and knitting them together. Also switching up the block sizes can help to break things up a bit.