The hydrophobic effect is really about water
Oil and water do not mix, and the reason is subtle. Water molecules near an oily surface cannot hydrogen-bond in every direction the way they like; they become more ordered, almost cage-like, to make the best of a bad situation. That ordering is costly. When two oily surfaces — a greasy part of your drug and a greasy wall of the pocket — come together, the trapped water between them is released back into the bulk, where it can tumble and bond freely again. The system gains disorder, and that gain drives binding. This is the hydrophobic effect.
Van der Waals: the reward for packing snugly
Once two surfaces are in contact, a second, gentler force takes over: the van der Waals interaction. Every atom has fluctuating electrons that momentarily polarize and attract neighboring atoms. Each such contact is tiny, but a pocket lined with many atoms snug against many atoms of the ligand adds up to a meaningful attraction. The key word is snug. Van der Waals attraction grows as atoms approach, but if they get too close they repel sharply. So the reward goes to a ligand whose shape fills the pocket precisely — bringing us back to shape complementarity. A molecule that leaves a void wastes contacts; one that bulges collides.
This is why a single well-placed methyl group can sometimes boost potency dramatically — it fills a small hydrophobic gap, displaces an unhappy water, and makes a handful of new van der Waals contacts, all at once. It is also why over-stuffing a pocket fails: push one atom too far and the steep repulsion erases everything you gained.
The greasiness trap
Because the hydrophobic effect is so reliable, the easiest way to make a compound more potent is to make it greasier — add rings, add lipophilic groups, raise the logP. This works in the assay and tempts everyone. The trap is that lipophilicity is also the single biggest driver of bad behavior elsewhere: poor solubility, promiscuous off-target binding, faster metabolism, and toxicity. Potency bought purely with grease is potency you will pay for later.
The craft, then, is to harvest the hydrophobic effect selectively — fill the specific pocket of your target with shape-matched, water-displacing atoms — rather than smearing lipophilicity across the whole molecule. Targeted grease wins potency and selectivity; bulk grease wins potency and trouble.