A method for analyzing the protein site similarity was devised aiming at understanding selectivity of homologous proteins and guiding the design of new drugs. The method is based on calculating Cα distances between s...A method for analyzing the protein site similarity was devised aiming at understanding selectivity of homologous proteins and guiding the design of new drugs. The method is based on calculating Cα distances between selected pocket residues and subsequent analysis by multivariate methods. Five closely related serine proteases, the coagulation factors II, VII, IX, X, and XI, were studied and their pocket similarity was illustrated by PCA clustering. OPLS-DA was then applied to identify the residues responsible for the variation. By combining these two multivariate methods, we could successfully cluster the different proteases according to class and identify the important residues responsible for the observed variation.展开更多
Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation...Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that increased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihydrobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible explanation of the counterintuitive results of TAM therapy.展开更多
Bleomycin (Blm) is a natural antibiotic with antitumour activity, used as a combination drug in treatment of various types of cancers. Blm intercalates with DNA and will in the presence of a redox metal ion and molecu...Bleomycin (Blm) is a natural antibiotic with antitumour activity, used as a combination drug in treatment of various types of cancers. Blm intercalates with DNA and will in the presence of a redox metal ion and molecular oxygen form an activated bleomycin complex capable of releasing free radicals and subsequently leading to DNA cleavage. The present theoretical work was carried out to better understand the interaction between DNA and Blm using different metal co-factors (Co and Fe). Binding energies and structural properties were analysed for both the complexes. The results show that Blm binds stronger to DNA when complexed with Fe, and provides a better structural orientation compared to the CoBlm complex in order to abstract the H4' hydrogen of deoxyribose that initiates the DNA strand cleavage process. The short distance between the iron-bound peroxide and the deoxyribose H4' furthermore supports the previously proposed direct abstraction mechanism.展开更多
文摘A method for analyzing the protein site similarity was devised aiming at understanding selectivity of homologous proteins and guiding the design of new drugs. The method is based on calculating Cα distances between selected pocket residues and subsequent analysis by multivariate methods. Five closely related serine proteases, the coagulation factors II, VII, IX, X, and XI, were studied and their pocket similarity was illustrated by PCA clustering. OPLS-DA was then applied to identify the residues responsible for the variation. By combining these two multivariate methods, we could successfully cluster the different proteases according to class and identify the important residues responsible for the observed variation.
文摘Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that increased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihydrobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible explanation of the counterintuitive results of TAM therapy.
文摘Bleomycin (Blm) is a natural antibiotic with antitumour activity, used as a combination drug in treatment of various types of cancers. Blm intercalates with DNA and will in the presence of a redox metal ion and molecular oxygen form an activated bleomycin complex capable of releasing free radicals and subsequently leading to DNA cleavage. The present theoretical work was carried out to better understand the interaction between DNA and Blm using different metal co-factors (Co and Fe). Binding energies and structural properties were analysed for both the complexes. The results show that Blm binds stronger to DNA when complexed with Fe, and provides a better structural orientation compared to the CoBlm complex in order to abstract the H4' hydrogen of deoxyribose that initiates the DNA strand cleavage process. The short distance between the iron-bound peroxide and the deoxyribose H4' furthermore supports the previously proposed direct abstraction mechanism.
