Evolutionary trace analysis of eukaryotic DNA topoisomerase I superfamily: identification of novel antitumor drug binding site.
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. The designed compounds may have novel scaffolds, thus will be helpful to overcome the toxicities of current camptothecin (CPT) 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 CPT, indicating suitable substitution of hydrophobic group on CPT will increase antitumor activity. The conservative residue Lys436 in the superfamily is of particular interest and new CPT 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 CPT resistance. As our molecular docking studies demonstrated they did not make any direct interaction with CPT, 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 novel highly potent CPT derivatives and virtual screening for novel lead compounds.
Song
Yunlong
Y
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
Qi
Yunpeng
Y
Zhang
Wannian
W
Sheng
Chunquan
C
Zhang
Min
M
Yao
Jianzhong
J
Yu
Jianxin
J
Miao
Zhenyuan
Z
Zhou
Youjun
Y
Zhu
Ju
J
Lü
Jiaguo
J
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001665:Binding Sites; D002166:Camptothecin / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D020539:Sequence Analysis, Protein; D059004:Topoisomerase I Inhibitors
D000596:Amino Acids; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin