When/whether to do pre-submission inquiry at high impact journals I'm curious to hear whether there is general guidance on when and whether to submit a pre-submission inquiry to a high impact journal (field: biology). Our goal is to identify a journal that will send our paper out for review. I understand pre-submissions are best when there really is a question of appropriateness, e.g., you are submitting a software-oriented manuscript to an experimental biology journal.

I am less clear on whether the current situation will benefit from a pre-submission inquiry. Consulting with my PI, and other faculty on the floor, there seems to be wide disagreements about the utility of pre-submission. Some argue these inquiries are more efficient than full submissions, since formatting a paper for each journal is usually time intensive. Others say they've had pre-submissions meet strong approval, then get editorially rejected. Any general thoughts on this?

Edit 6.27.15.
I'd like to specifically highlight bitwise' comment below as that has proven to be the most useful advice. In the last 9 months I've submitted multiple articles not fulfilling the exact formatting requirements, length limits, supplement guidelines, and even figure guidelines, and this has not seemed to affect whether we get reviewed. One paper is currently under review at Molecular Cell that is 4000 characters over limit and has a wildly incorrectly formatted supplement, and 1 figure over the limit.
I have never found a pre-submission inquiry to be useful, and was always advised against it. The main argument is that it does not increase your chances of acceptance and just adds another hurdle to pass. Additionally, assuming you use a reference manager the difference in formatting between journals is usually minimal (or you can ignore some of the rules on your first submission).

However, I always submitted to journals that I know and read before, so I knew that the topic is generally appropriate. I would only consider a pre-submission inquiry if I am not sure whether the general topic is appropriate for the journal.