Muttaqin et al Journal of Drug Delivery & Therapeutics. 2021; 11(6-S):70-78 ISSN: 2250-1177 [70] CODEN (USA): JDDTAO Available online on 15.12.2021 at http://jddtonline.info Journal of Drug Delivery and Therapeutics Open Access to Pharmaceutical and Medical Research Copyright © 2021 The Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited Open Access Full Text Article Research Article Study of Molecular Docking, Molecular Dynamic and Toxicity Prediction of Several Quinoline Alkaloid Derivatives as a Bruton Tyrosine Kinase Inhibitor as Anti-Leukemia Muttaqin, Fauzan Zein 1,2 *; Restisari, Ikma Hanifah 2 ; Muhammad, Hubbi Nasrullah 3 1 Faculty of Pharmacy, Bhakti Kencana University, Bandung, West Java, 40614, Indonesia 2 Bandung School of Pharmacy, Bandung, West Java, 40614, Indonesia 3 School of Pharmacy, Bandung Institute of Technology, Bandung, West Java, 40132, Indonesia Article Info: _________________________________________ Article History: Received 17 October 2021 Reviewed 02 December 2021 Accepted 08 December 2021 Published 15 December 2021 _________________________________________ Cite this article as: Muttaqin FZ, Restisari IH, Muhammad HN, Study of Molecular Docking, Molecular Dynamic and Toxicity Prediction of Several Quinoline Alkaloid Derivatives as a Bruton Tyrosine Kinase Inhibitor as Anti-Leukemia, Journal of Drug Delivery and Therapeutics. 2021; 11(6-S):70-78 DOI: http://dx.doi.org/10.22270/jddt.v11i6-S.5135 _________________________________________ *Address for Correspondence: Muttaqin, Fauzan Zein, Faculty of Pharmacy, Bhakti Kencana University, Bandung, West Java, 40614, Indonesia Abstract ______________________________________________________________________________________________________ Quinoline alkaloid and its derivatives play a vital role in the development of new therapeutic agents. Cinnoline structure has similarities with quinoline alkaloid compound and has the potential to inhibit Bruton’s Tyrosine Kinase (BTK) in leukemia treatment. This research aims to study the interaction of several quinoline alkaloids with BTK and to predict the toxicity to ensure their safety. This study was carried out using computational studies, including molecular docking, molecular dynamics simulation, and toxicity prediction, to assess the compound’s activity towards BTK and their toxicity. Molecular docking simulations showed that ten compounds (S1, S2, S4, S5, S8, S13, S14, S16, S17, and S20) had the best affinity to BTK. Molecular dynamics simulations to these ten compounds showed that only seven compounds (S1, S5, S8, S13, S16, S17, and S20) could stabilize the interaction towards BTK with RMSD and RMSF value of 0.5 ± 2 Å and 0.5 ± 6, 5 Å, respectively. Toxicity prediction results showed that these quinoline alkaloids had various toxicity characteristics, but most were not carcinogens and mutagens (S4, S5, S6, S7, S8, S10 S11, S12, S14, and S15). It can be concluded that Yukositrin (S8) has the most potential affinity towards BTK, which can be used as anti-leukemia with low toxicity. Keywords: anti-leukemia, Bruton Tyrosine Kinase, docking, MD, quinoline alkaloids INTRODUCTION Cancer is a disease with a high prevalence and is the second- highest disease in the world after heart disease. In Indonesia, cancer is a dreaded disease because it is difficult to cure and causes many deaths. Cancer risk factors such as genetics, carcinogens, and lifestyle behaviors lead to nearly 1.4%, or about 347,792 of all cancer cases 1 . In the previous research, we found some potential anticancer drug candidate compounds 2 . Some of the leukemia treatments currently used are surgery and drug treatment. The death rate from leukemia reaches 9.8%, and leukemia recurrence approaches 5.3%. This is due to the lack of available treatments. One of the leukemia treatments is the use of ibrutinib 3 . Ibrutinib is the primary choice in chronic lymphocytic leukemia treatment and is one of the potent drugs in leukemia treatment that acts as a Bruton’s Tyrosine Kinase (BTK) inhibitor 4,5 . BTK plays an essential role in the B cell signaling process, especially in the B leukocytes cell proliferase 6,7 . Some studies suggest that other synthetic derivatives can inhibit BTK, namely GDC-0834. GDC-0834 has the same bonding position as ibrutinib (PCI-32765), occupying three inhibition positions on BTK receptor 8 . Another study suggests that the presence of small molecules, called cinnoline, is known to have the potential to inhibit BTK by occupying one position of inhibitory bonding 9 . Cinnoline structure has similarities with quinoline alkaloid compound, based on applying the Structure-Activity Relationship (SAR) principle 10 . In this study, we conducted in silico study of some quinoline alkaloid derivatives as Bruton’s Tyrosine Kinase inhibitor by docking and MD for the development of antileukemia drugs. MATERIALS AND METHODS Docking, molecular dynamic, and ADMET studies were performed for all designed compounds by Gaussian 09, AutoDock4 and AutoDockTools4, GROMACS, and ADMET PredictorTM installed in a single machine running on a 3.4 GHz Intel (R) Core(TM) i7-6700 processor with 16 GB RAM, 4 GB VGA, and 500 GB hard disk with dual-boot Microsoft Windows 7 Pro 64 bit and Linux Ubuntu as the operating system.