title: The binding modes and binding affinities of epipodophyllotoxin derivatives with human topoisomerase IIα.
abstract: Epipodophyllotoxin derivatives have important therapeutic value in the treatment of human cancers. These drugs kill cells by inhibiting the ability of topoisomerase II (TP II) to ligate nucleic acids that it cleaves during the double-stranded DNA passage reaction. The 3D structure of human TP IIα was modeled by homology modeling. A virtual library consisting of 143 epipodophyllotoxin derivatives has been developed. Their molecular interactions and binding affinities with modeled human TP IIα have been studied using the docking and Bimolecular Association with Energetics (eMBrAcE) developed by Schrödinger. Structure activity relationship models were developed between the experimental activity expressed in terms of percentage of intracellular covalent TP II-DNA complexes (log PCPDCF) of these compounds and molecular descriptors like docking score and free energy of binding. For both the cases the r2 was in the range of 0.624-0.800 indicating good data fit and r2(cv) was in the range of 0.606-774 indicating that the predictive capabilities of the models were acceptable. Low levels of root mean square error for the majority of inhibitors establish the docking and eMBrAcE based prediction model as an efficient tool for generating more potent and specific inhibitors of human TP IIα by testing rationally designed lead compounds based on epipodophyllotoxin derivatization.
authors.affiliation: Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Distt. Solan 173215, Himachal Pradesh, India. pknaik73@rediffmail.com
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Naik
authors.forename: Abhishek
authors.initials: A
authors.lastname: Dubey
authors.forename: Komal
authors.initials: K
authors.lastname: Soni
authors.forename: Rishay
authors.initials: R
authors.lastname: Kumar
authors.forename: Harvinder
authors.initials: H
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004247:DNA; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin