Systematic identification of activity cliffs with dual-atom replacements and their rationalization on the basis of single-atom replacement analogs and X-ray structures.

Very small chemical changes in active compounds causing large potency effects are of particular interest in medicinal chemistry and drug design. We have systematically searched active compounds with available high-confidence activity data for pairs of structural analogs with dual-atom replacements and additional analogs with corresponding single-atom replacements. From ~287,000 unique qualifying compounds with activity against nearly 1900 unique targets, ~3500 target-based analog pairs with dual-atom replacements were identified. These included 852 pairs with significant differences in compound potency, representing a set of previously unobserved activity cliffs. Comparing these pairs with corresponding single-atom replacement analogs, which were frequently identified, made it possible to systematically analyze how potency changes propagated from single- to dual-atom replacements. The analysis uncovered different potency effects and revealed that individual atom replacements were often decisive for activity cliff formation. For a limited number of activity cliffs, X-ray structures of targets in complex with cliff compounds were available, which aided in rationalizing potency alterations among analogs with single- or dual-atom replacements. The analog pairs identified herein provide a rich resource of structure-activity relationship information and attractive test cases for calibrating computational methods.