Determination of Novel Anti-Cancer Agents by Targeting OGG1 Enzyme Using Integrated Bioinformatics Methods

Ziyad Tariq Muhseen, Mustafa Hussein Ali, Nawar Rushdi Jaber, Dheyaa Shakir Mashrea, Ali Mamoon Alfalki and Guanglin Li
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Ziyad Tariq Muhseen: School of Life Sciences, Shaanxi Normal University, Xi’an 710062, China
Mustafa Hussein Ali: School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Nawar Rushdi Jaber: Department of Medical Laboratory Techniques, School of Life Sciences, Dijlah University College, Baghdad 00964, Iraq
Dheyaa Shakir Mashrea: Educational Directorate of Babylon Province, Ministry of Education, Babylon 51002, Iraq
Ali Mamoon Alfalki: Department of Health Professional Graduate, University of New England, Biddeford, Portland, ME 04005, USA
Guanglin Li: School of Life Sciences, Shaanxi Normal University, Xi’an 710062, China

IJERPH, 2021, vol. 18, issue 24, 1-17

Abstract: The 8 -oxoguanine DNA glycosylase (OGG1) enzyme is a key DNA glycosylase mediating the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA molecule to the start base excision repair pathway. The OGG1 glycosylase function depletion has been seen to obstruct pathological conditions such as inflammation, A3 T-cell lymphoblastic acute leukemia growth, and neurodegenerative diseases, thus warranting OGG1 as an attractive anti-cancer enzyme. Herein, we employed several drug libraries intending to screen non-toxic inhibitory molecules against the active pocket of the enzyme that achieved stable binding mode in dynamics. Two anti-cancer compounds ([O-]C1=C(CC2=CC=CC=C2)SC(=[N+]1CC(=O)NC3=NC=C(CC4=CC=CC=C4)S3)S and CCCN(CCC)[S]-(=O)(=O)C1=CC=C(C=C1)C(=O)NNC2=NC3=CC=C(Br)C=C3C(=N2)C4=CC=CC=C4) from Selleckchem.com were identified to occupy the active pocket of OGG1 and bind with greater affinity than Control TH5487. The binding affinity of Top-1 is −11.6 kcal/mol while that of Top-2 is −10.7 kcal/mol in contrast to TH5487 Control (−9 kcal/mol). During molecular dynamic simulations versus time, the said compounds are tightly held by the enzyme with no minor structural deviations reported except flexible loops in particular those present at the N and C-terminal. Both the compounds produced extensive hydrophobic interactions with the enzyme along with stable hydrogen bonding. The docking and molecular dynamics simulations predictions were further validated by molecular mechanics with generalized Born and surface area solvation (MM/GBSA) and Poisson Boltzmann surface area (MM/PBSA), and WaterSwap binding energies that validated strong binding of the compounds to the enzyme. The MM/GBSA binding free energy for Top-1 complex is −28.10 kcal/mol, Top-2 complex is −50.14 kcal/mol) and Control is −46.91 kcal/mol while MM/PBSA value for Top-1 , Top-2 and Control is −23.38 kcal/mol, −35.29 kcal/mol and −38.20 kcal/mol, respectively. Computational pharmacokinetics support good druglike candidacy of the compounds with acceptable profile of pharmacokinetics and very little toxicity. All these findings support the notion that the compounds can be used in experiments to test their anti-cancer activities.

Keywords: base excision repair; binding free energies; glycosylase inhibitor; MD simulations; molecular docking; TH5487 (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2021
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