Non-Competitive Inhibitors
Unlike their competitive cousins, non-competitive inhibitors don't bother trying to fit into the active site. Instead, they're much more devious - they bind to a completely different spot called the allosteric site.
When a non-competitive inhibitor attaches to this allosteric site, it distorts the enzyme's tertiary structure. This changes the shape of the active site, meaning the substrate can no longer fit properly - it's like changing the lock so the key won't work anymore.
The key difference here is that increasing substrate concentration won't help overcome this type of inhibition. The active site is permanently altered, so it doesn't matter how many substrate molecules you throw at it. Many non-competitive inhibitors create permanent changes, except for those involved in metabolic pathways where the cell needs more control.
Remember: Non-competitive = different site, permanent change. No amount of extra substrate will fix a broken lock!