Evolutionary trace analysis of eukaryotic DNA topoisomerase I superfamily: Identification of novel antitumor drug binding site

摘要

The studies of novel inhibitors of DNA topoisomerase I (Topo I) have already become very promising in cancer chemotherapy. Identifying the new drug-binding residues is playing an important role in the design and optimization of Topo I inhibitors. Thedesigned compounds may have novel scaffolds, thus will be helpful to overcome the toxicities of current camptothecin (CRT) drugs and may provide a solution to cross resistance with these drugs. Multiple sequence alignments were performed on eukaryotic DNA topoisomerase I superfamily and thus the evolutionary tree was constructed. The Evolutionary Trace method was applied to identify functionally important residues of human Topo I. It has been demonstrated that class-specific hydrophobic residues Ala351,Met428, Pro431 are located around the 7,9-position of CRT, indicating suitable substitution of hydrophobic group on CRT will increase antitumor activity. The conservative residue Lys436 in the superfamily is of particular interest and new CRT derivatives designed based on this residue may greatly increase water solubility of such drugs. It has also been demonstrated that the residues Asn352 and Arg364 were conservative in the superfamily, whose mutation will render CRT resistance. As our molecular docking studies demonstrated they did not make any direct interaction with CRT, they are important drug-binding site residues for future design of novel non-camptothecin lead compounds. This work provided a strong basis for the design and synthesis of novelhighly potent CRT derivatives and virtual screening for novel lead compounds.