title: DNA topoisomerase-directed anticancerous alkaloids: ADMET-based screening, molecular docking, and dynamics simulation.
abstract: Topoisomerases (Topo I and II) have been looked as crucial targets against various types of cancers. In the present paper, 100 anticancerous alkaloids were subjected to in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses to investigate their pharmacokinetic properties. Out of 100 alkaloids, only 18 were found to fulfill all the ADMET descriptors and obeyed the Lipinski's rule of five. All the 18 alkaloids were found to dock successfully within the active site of both Topo I and II. A comparison of the inhibitory potential of 18 screened alkaloids with those of selected drugs revealed that four alkaloids (oliveroline, coptisine, aristolactam, and piperine) inhibited Topo I, whereas six alkaloids (oliveroline, aristolactam, anonaine, piperine, coptisine, and liriodenine) inhibited Topo II more strongly than those of their corresponding drugs, topotecan and etoposide, respectively, with oliveroline being the outstanding. The stability of the complexes of Topo I and II with the best docked alkaloid, oliveroline, was further analyzed using 10 nSec molecular dynamics simulation and compared with those of the respective drugs, namely, topotecan and etoposide, which revealed stabilization of these complexes within 5 nSec of simulation with better stability of Topo II complex than that of Topo I.
authors.affiliation: Department of Biochemistry, Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.|Amity Institute of Biotechnology, Amity University, Lucknow, Uttar Pradesh, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.
authors.forename: Tamal
authors.initials: T
authors.lastname: Das
authors.affiliation: Department of Biochemistry, Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.
authors.forename: Manika
authors.initials: M
authors.lastname: Awasthi
authors.affiliation: Department of Biochemistry, Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.
authors.forename: Veda P
authors.initials: VP
authors.lastname: Pandey
authors.affiliation: Amity Institute of Biotechnology, Amity University, Lucknow, Uttar Pradesh, India.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Pandey
authors.affiliation: Department of Biochemistry, Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, University of Lucknow, Lucknow, Uttar Pradesh, India.
authors.forename: Upendra N
authors.initials: UN
authors.lastname: Dwivedi
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D059003:Topoisomerase Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: ADMET screening; anticancerous alkaloids; docking; molecular dynamics simulation; topoisomerases