Kairi Furui, Masahito Ohue
PairMap2 is a web application for testing intermediate-molecule insertion in relative binding free energy calculations. Transformations between structurally distant ligands can have insufficient overlap in free-energy space, leading to poor convergence and unreliable predictions. PairMap2 reimplements the PairMap intermediate-insertion workflow as a browser-based tool and supports two-molecule path analysis and multiligand perturbation-map construction. The interface visualizes perturbation networks, generated intermediates, and maximum common substructure-based atom mappings. In nine benchmark cases from the original PairMap study, PairMap2 completed faster in eight cases; for an additional low-similarity transformation (lead optimization mapper (LOMAP) similarity score 0.0111), it achieved an approximately 19.6-fold speedup. PairMap2 enables computational chemists to assess intermediate insertion before free energy perturbation FEB calculations without setting up a local execution environment.