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Matched molecular pair analysis (MMPA), a promising tool to efficiently extract and summarize the relationship between structural transformation and property change, is suitable for local structural optimization tasks. Especially, the integration of MMPA with QSAR modeling can further strengthen the utility of MMPA in molecular optimization navigation. In this study, a new semi-automated procedure based on KNIME was developed to support MMPA on both large- and small-scale datasets, including molecular preparation, QSAR model construction, applicability domain evaluation, and MMP calculation and application. 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