Abstract 2926: Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules

Abstract

Abstract The compounds CM03 and SOP1812 are tri- and tetra-substituted naphthalene diimide derivatives with high affinity for several human DNA quadruplexes. They have been designed by computer modelling based on co-crystal structures of 1st-generation substituted naphthalene diimides with human intramolecular telomeric quadruplexes. CM03 and SOP1812 have single-digit 1-20 nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Marchetti et al., J. Med. Chem, 2018, 61, 2500-2517: Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in animal models. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. The role of water in protein-drug binding is well documented and known to be important for accurate estimates of drug binding energies and for docking/virtual screening studies. To date this factor has not been seriously considered in studies of ligand-quadruplex interactions even though virtual screening has emerged as an important tool for finding new chemotypes and optimizing compound libraries in silico. A high-resolution crystal structure of a naphthalene diimide quadruplex complex (PDB id 3UYH: Micco et al., J. Med. Chem., 2013, 56, 2959-2974) has now been analyzed in detail. Patterns of water molecules have been found in each of the four quadruplex grooves, associated with the cationic side chains. Only a nitrogen atom on each N-methyl-piperazine cationic end groups is in direct hydrogen bonded contact with a phosphate group. The morpholino groups each have a small and well-defined cluster of water molecules mediating between cationic nitrogen atom and phosphate group. The rest of each groove is filled by a second cluster of waters, suggesting that larger substituents can be accommodated. Data from a library of naphthalene diimide derivatives is being examined to validate the role of these waters, especially with respect to their relative mobilities and ease of displacement. Citation Format: Stephen Neidle. Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2926.