TGSA-Flex: Extending the capabilities of the Topo-Geometrical superposition algorithm to handle flexible molecules

In this work, an extension of the already studied Topo-Geometrical Superposition Approach (TGSA) is presented. TGSA, a general-purpose, fast, automatic, and user-intuitive three-dimensional molecular alignment procedure, was originally designed to superpose rigid molecules simply based on atomic numbers, molecular coordinates, and connectivity. The algorithm is further developed to enable handling rotations around single bonds; in this way, common structural features, which were not properly aligned due to conformational causes, can be brought together, thus improving the molecular similarity picture of the final alignment. The present procedure, implemented in Fortran 90 and named TGSA-Flex, is deeply detailed and tested over four molecular sets: amino acids, nordihydroguaiaretic acid (NDGA) derivatives, HIV-1 protease inhibitors, and 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives. TGSA-Flex performance is evaluated by means of computational time, number of superposed atoms (also comparing it with respect to the rigid approach), and index of fit between the compared structures.