The studies of novel inhibitors of DNA topoisomerase I(Topo I)have already be-come very promising in cancer chemotherapy.Identifying the new drug-binding residues is playing an important role in the design and optimiz...The studies of novel inhibitors of DNA topoisomerase I(Topo I)have already be-come 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 com-pounds 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.Mul-tiple sequence alignments were performed on eukaryotic DNA topoisomerase I superfamily and thus the evolutionary tree was constructed.The Evolutionary Trace method was applied to iden-tify 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,indi-cating 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.展开更多
Structural analysis of known drugs or drug-like compounds provides important information for drug design. The 142553 drug molecules in the MDL Drug Data Report database were analyzed, and then the common structural fe...Structural analysis of known drugs or drug-like compounds provides important information for drug design. The 142553 drug molecules in the MDL Drug Data Report database were analyzed, and then the common structural features were extracted. According to the common structural features, drug molecules were segmented into 32017 fragments, including 13642 ring fragments, 10076 linker fragments, and 8299 side chain fragments. These fragments were further used to establish three types of virtual combinatorial fragment libraries: a basic framework library containing 13574 rings; a linker library of 8051 linkers and a pharmacophore library of 34244 fragments combined by rings and side chains. After energy minimization, all fragments in the above three libraries maintain reasonable geometrical features and spatial conformations, and would be useful for building a virtual combinatorial database and de novo drug design.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grant No.30371689)the Nat ional“973”Fundamental Research Projects of China(Grants No.G1998051104).
文摘The studies of novel inhibitors of DNA topoisomerase I(Topo I)have already be-come 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 com-pounds 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.Mul-tiple sequence alignments were performed on eukaryotic DNA topoisomerase I superfamily and thus the evolutionary tree was constructed.The Evolutionary Trace method was applied to iden-tify 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,indi-cating 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.
基金Supported by the National Natural Science Foundation of China (Grant No. 30430750)National 863 Project (Grant No. 2002AA233091)
文摘Structural analysis of known drugs or drug-like compounds provides important information for drug design. The 142553 drug molecules in the MDL Drug Data Report database were analyzed, and then the common structural features were extracted. According to the common structural features, drug molecules were segmented into 32017 fragments, including 13642 ring fragments, 10076 linker fragments, and 8299 side chain fragments. These fragments were further used to establish three types of virtual combinatorial fragment libraries: a basic framework library containing 13574 rings; a linker library of 8051 linkers and a pharmacophore library of 34244 fragments combined by rings and side chains. After energy minimization, all fragments in the above three libraries maintain reasonable geometrical features and spatial conformations, and would be useful for building a virtual combinatorial database and de novo drug design.
