There are 2 scripts that can be responsible for a large portion of the queries. If any of your users are viewing the postlist script in expanded mode this will end up creating a large number of queries. showthreaded also has this as well as it needs to do all the queries for all the replies.
Unfortunately there are only so many tweaks you can make to mysql or the scripts to improve performance. Normally when it gets to a certain point the server itself becomes the bottleneck to keep up with that many users.
What you really need to run is something like top when the server is under normal load and under heavy load. This will give you alot of info on what is slowing the system down. It could be that it is starting to swap memory, which means that memory is an issue. It could be that certain processes are taking up all of the CPU time. top is one of the most valuable tools you can use when the system starts to slow down.
