Molecular Docking Studies for the Identification of Novel APOBEC3B Inhibitors using Different Docking Routines

Abstract

Event Abstract Back to Event Molecular docking studies for the identification of novel APOBEC3B inhibitors using different docking routines Nor A. Jusril1, 2, Shahrul I. Abu Bakar1, 2, Mohd I. Adenan1 and Ng K. Wen1, 2, 3* 1 Faculty of Applied Sciences, Universiti Teknologi Mara, Malaysia 2 Atta-ur-Rahman Institute for Natural Product Discovey, Universiti Teknologi MARA, Malaysia 3 Centre of Foundation Studies, Universiti Teknologi MARA, Malaysia Background Overexpression of the enzyme APOBEC3B (A3B) DNA cytosine deaminase is an inciting factor for tumor progression across a range of cancer types. Dysregulation of A3B results in C-to-T or C-to-G mutations during cellular replication. Evidence of A3B association with proliferation related to oncogenes, replication stress, and drug sensitivity of cancer cells are well-documented. Consequently, therapeutic interventions using small molecules in the modulation of A3B could provide opportunities for cancer prevention or treatment. The present study seeks to narrow down prospective chemical scaffolds that could interact with the A3B enzyme, using computer-aided methods. Methods Molecular docking and virtual screening of 2000 compounds of diverse structures were performed using an open source modelling simulation software programs, AutoDock, Vina, and Gold. The molecular models of each compound were constructed and optimized prior to the docking simulations against A3B (PDB ID: 5TD5). Docking parameters, such as grid dimension, run repetition, and types of algorithms used, were ameliorated to ensure accuracy in the virtual screening. A combination of scoring, minimization, and redocking using the software programs on the drug libraries set was employed to select active compounds through rapid gradient-optimization conformational search. The results were then compared to the outcome from software programs, which ranked the active compounds using rapid Lamarckian genetic algorithm search method and empirical free energy force field. Results Seven hit compounds with high scoring from docking the software which contain fewer than five rigid and rotatable bonds, having tendency to be planar, with one or less chiral centres and pharmacologically desirable features, were identified. These compounds were ranked highest among the 2000 structures in the simulation scoring and have an indistinguishable binding energy profile with A3B. Conclusions A total of seven promising small inhibitor molecules of A3B enzymatic activities were identified. The findings from this project should significantly shorten the time in the designing the first-in-class novel molecules against the A3B, as well as for subsequent in vitro and in vivo studies. Acknowledgements This work was supported by Bestari Research Grant (Bestari grant no: 600-IRMIPERDANA 5/3 BESTARI (072/2018) from the Institute of Research Management and Innovation (IRMI), Universiti Teknologi MARA. We would like to thank the Atta-ur-Rahman Institute for Natural Product Discovery for providing computing resources and the docking program. Keywords: molecular simulation and docking, Cancer, inhibitors, Software, APOBEC3B Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Oral Presentation Topic: Cancer Citation: Jusril NA, Abu Bakar SI, Adenan MI and Wen NK (2019). Molecular docking studies for the identification of novel APOBEC3B inhibitors using different docking routines. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00044 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Nov 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Ng K Wen, Faculty of Applied Sciences, Universiti Teknologi Mara, Shah Alam, Selangor Darul Ehsan, 40450, Malaysia, kwokwen.ng@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nor A Jusril Shahrul I Abu Bakar Mohd I Adenan Ng K Wen Google Nor A Jusril Shahrul I Abu Bakar Mohd I Adenan Ng K Wen Google Scholar Nor A Jusril Shahrul I Abu Bakar Mohd I Adenan Ng K Wen PubMed Nor A Jusril Shahrul I Abu Bakar Mohd I Adenan Ng K Wen Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.