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Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin.
J Med Chem. 1998 Jun 18; 41(13):2216-26.JM

Abstract

The present studies provide a three-dimensional model for the postulated ternary cleavable complex of topoisomerase I (top1), DNA, and camptothecin (CPT). Molecular simulations were done using the AMBER force field. The results suggest that a ternary cleavable complex might be stabilized by several hydrogen bonds in the binding site. In this proposed "drug-stacking" model, CPT is pseudointercalated in the top1-linked DNA cleavage site and interacts with the protein near its catalytic tyrosine through hydrogen bonding and stacking. The structural model is consistent with the following experimental observations: (i) the N3 position of the 5' terminal purine of the cleaved DNA strand is readily alkylated by 7-chloromethyl 10,11-methylenedioxy CPT; (ii) CPT generally tolerates substituents at positions 7, 9, and 10 but is inactivated by additions at position 12; (iii) 10,11-methylenedioxy (MDO) CPT is much more potent than 10,11-dimethoxy (DMO) CPT; (iv) the lactone portion of CPT is essential for top1 inhibitory activity; (v) 20S derivatives of CPT are much more potent than the 20R analogues; (vi) a catalytic tyrosine hydroxyl in top1 covalently links to the 3' terminal base, T, of the cleaved DNA strand; and (vii) top1 mutation Asn722Ser leads to CPT resistance. A total of 18 camptothecin derivatives with different DNA cleavage potencies were docked into the hypothetical cleavable complex binding site to test and refine the model. These studies provide insight into a possible mechanism of top1 inhibition by CPT derivatives and suggest rational approaches for the design of new CPT derivatives.

Authors+Show Affiliations

Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Building 37, Room 5D02, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9632354

Citation

Fan, Y, et al. "Molecular Modeling Studies of the DNA-topoisomerase I Ternary Cleavable Complex With Camptothecin." Journal of Medicinal Chemistry, vol. 41, no. 13, 1998, pp. 2216-26.
Fan Y, Weinstein JN, Kohn KW, et al. Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. J Med Chem. 1998;41(13):2216-26.
Fan, Y., Weinstein, J. N., Kohn, K. W., Shi, L. M., & Pommier, Y. (1998). Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. Journal of Medicinal Chemistry, 41(13), 2216-26.
Fan Y, et al. Molecular Modeling Studies of the DNA-topoisomerase I Ternary Cleavable Complex With Camptothecin. J Med Chem. 1998 Jun 18;41(13):2216-26. PubMed PMID: 9632354.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. AU - Fan,Y, AU - Weinstein,J N, AU - Kohn,K W, AU - Shi,L M, AU - Pommier,Y, PY - 1998/6/19/pubmed PY - 1998/6/19/medline PY - 1998/6/19/entrez SP - 2216 EP - 26 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 41 IS - 13 N2 - The present studies provide a three-dimensional model for the postulated ternary cleavable complex of topoisomerase I (top1), DNA, and camptothecin (CPT). Molecular simulations were done using the AMBER force field. The results suggest that a ternary cleavable complex might be stabilized by several hydrogen bonds in the binding site. In this proposed "drug-stacking" model, CPT is pseudointercalated in the top1-linked DNA cleavage site and interacts with the protein near its catalytic tyrosine through hydrogen bonding and stacking. The structural model is consistent with the following experimental observations: (i) the N3 position of the 5' terminal purine of the cleaved DNA strand is readily alkylated by 7-chloromethyl 10,11-methylenedioxy CPT; (ii) CPT generally tolerates substituents at positions 7, 9, and 10 but is inactivated by additions at position 12; (iii) 10,11-methylenedioxy (MDO) CPT is much more potent than 10,11-dimethoxy (DMO) CPT; (iv) the lactone portion of CPT is essential for top1 inhibitory activity; (v) 20S derivatives of CPT are much more potent than the 20R analogues; (vi) a catalytic tyrosine hydroxyl in top1 covalently links to the 3' terminal base, T, of the cleaved DNA strand; and (vii) top1 mutation Asn722Ser leads to CPT resistance. A total of 18 camptothecin derivatives with different DNA cleavage potencies were docked into the hypothetical cleavable complex binding site to test and refine the model. These studies provide insight into a possible mechanism of top1 inhibition by CPT derivatives and suggest rational approaches for the design of new CPT derivatives. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9632354/Molecular_modeling_studies_of_the_DNA_topoisomerase_I_ternary_cleavable_complex_with_camptothecin_ L2 - https://dx.doi.org/10.1021/jm9605445 DB - PRIME DP - Unbound Medicine ER -