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Tytuł:
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Ligand-based design approach of potential Bcl-2 inhibitors for cancer chemotherapy.
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Autorzy:
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Arakal NG; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Sharma V; Department of Pharmaceutics, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Kumar A; Department of Pharmacology, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Kavya B; Department of Pharmacology, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Devadath NG; Department of Pharmacology, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India.
Kumar SB; Department of Biotechnology, M S Ramaiah Institute of Technology, Bangalore, India.
Murthy KT; Department of Biotechnology, M S Ramaiah Institute of Technology, Bangalore, India.
Murahari M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore, India. Electronic address: .
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Źródło:
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Computer methods and programs in biomedicine [Comput Methods Programs Biomed] 2021 Sep; Vol. 209, pp. 106347. Date of Electronic Publication: 2021 Aug 08.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Limerick : Elsevier Scientific Publishers
Original Publication: Amsterdam : Elsevier Science Publishers, c1984-
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MeSH Terms:
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Neoplasms*/drug therapy
Quantitative Structure-Activity Relationship*
Animals ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Rats
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Contributed Indexing:
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Keywords: Anticancer; AutoQSAR; Bcl-2; Hit compounds; Ligand-based design
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Substance Nomenclature:
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0 (Ligands)
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Entry Date(s):
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Date Created: 20210816 Date Completed: 20210914 Latest Revision: 20210914
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Update Code:
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20240104
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DOI:
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10.1016/j.cmpb.2021.106347
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PMID:
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34399152
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Background and Objectives: Overexpression of prosurvival Bcl-2 family members make tumor cells resistant to conventional cancer therapeutic agents. It is commonly observed feature in many different types of human tumors. Hence, small-molecules as Bcl-2 inhibitors may have a promising therapeutic potential for the treatment of human cancer. The given study focusses on development of novel and small Bcl-2 inhibitors using ligand-based drug design approach.
Methods: Ligand based pharmacophore was generated using the PHASE tool of Schrödinger and screened ZINC database through ZINCPharmer webserver to identify compounds with similar features. Compounds having good fitness score were selected for molecular docking and binding interactions were compared with drugs in market as well as trials. QSAR model was generated using advanced AutoQSAR tool and validated for prediction of unknown compounds. QSAR prediction of in silico active identified three potential compounds and were subjected to investigate stability by molecular dynamics simulations and MM-PBSA binding energy calculations.
Results: Study identified three in silico potential molecules with good stability and binding affinity. Further substructure search and pIC 50 value prediction has identified six more molecules. Total nine molecules have demonstrated good drug likeness features.
Conclusion: Final oral rat LD50 calculation of nine molecules has identified three hit molecules i.e., ZINC76760927, ZINC76768675 and ZINC52767796 for further in vitro and in vivo testing as safe and potential Bcl-2 inhibitors.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
