 Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as either synergistic or antagonistic, depending on whether the observed combination response deviates from the expected effect calculated based on a reference model of non-interaction. Existing reference models were developed for low throughput drug combination experiments, making them incompatible with the complex drug interactions observed in large-scale dose-response matrix experiments. To address this limitation, we proposed a new reference model called zero interaction potency, ZIP. This model captures the drug interaction relationships by comparing the change in potency of the dose-response curve between individual drugs and their combinations. We used a delta score to measure the deviation from the expectation of no interaction and proved that a delta score of zero indicates both probabilistic independence and dose additivity. We then applied this model to a large-scale anti-cancer drug combination experiment, demonstrating its ability to capture the experimentally confirmed drug synergy while maintaining a low-false positive rate. Additionally, we proposed using an interaction landscape over the entire dose-response matrix to identify and quantify synurg. This article was authored by Bugvon Yadav, Krista Wennerberg, Taro Adokaleo, and others. We are article.tv, links in the description below.