Computational Study of Anticancer Drug Resistance Caused by 10 Topisomerase I Mutations, Including 7 Camptothecin Analogs and Lucanthone

• Published in: Journal of chemical information and modeling 2016-09, Vol.56 (9), p.1872-1883
• Main Authors: Mulholland, Kelly, Wu, Chun
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Binding sites; Camptothecin - chemistry; Camptothecin - metabolism; Camptothecin - pharmacology; Cancer; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type I - genetics; DNA Topoisomerases, Type I - metabolism; Drug resistance; Drug Resistance, Neoplasm - genetics; Humans; Lucanthone - chemistry; Lucanthone - metabolism; Lucanthone - pharmacology; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutation; Protein Conformation; Sequence Homology, Amino Acid; Simulation; Thermodynamics
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.6b00317

Although Camptothecin and its analogs as Topoisomerase I poisons can effectively treat cancers, serious drug resistance has been identified for this class of drugs. Recent computational studies have indicated that the mutations near the active binding site of the drug can significantly weaken the drug binding and cause drug resistance. However, only Topotecan and three mutations have been previously analyzed. Here we present a comprehensive binding study of 10 Topoisomerase I mutants (N722S, N722A, D533G, D533N, G503S, G717V, T729A, F361S, G363C, and R364H) and 8 poisons including 7 Camptothecin analogs as well as a new generation Topoisomerase I drug, Lucanthone. Utilizing Glide docking followed by MMGBSA calculations, we determined the binding energy for each complex. We examine the relative binding energy changes with reference to the wild type, which are linked to the degree of drug resistance. On this set of mutant complexes, Topotecan and Camptothecin showed much smaller binding energies than a set of new Camptothecin derivatives (Lurtotecan, SN38, Gimatecan, Exatecan, and Belotecan) currently under clinical trials. We observed that Lucanthone exhibited comparable results to Topotecan and Camptothecin, indicating that it may serve as a promising candidate for future studies as a Topoisomerase I poison. Our docked results on Topotecan were also validated by a set of molecular dynamics simulations. In addition to a good agreement on the MMGBSA binding energy change, our simulation data also shows there is larger conformation fluctuation upon the mutations. These results may be utilized to further advancements of Topoisomerase I drugs that are resistant to mutations.