Molecular Docking Investigation of New Inhibitors of <i>Falciparum vivax</i>

作     者：Kassim Adebambo Sinthusan Gunaratnam 

作者机构：Pharmaceutical Chemistry Unit Department of Pharmacy Pharmacology and Postgraduate Medicine University of Hertfordshire Hatfield UK 

出 版 物：《Computational Molecular Bioscience》 (计算分子生物学（英文）)

年 卷 期：2018年第8卷第2期

页      面：43-67页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Falciparum vivax Hydrogen Bond Interaction Molecular Docking Lipinski’s Rule N-Myristoyltransferase (PvNMT) 

摘      要：Despite the vigorous research and development, as of 2017, there is currently no widely available antimalarial vaccine. An effective, commercially available vaccine would be a huge game changer;however, it seems like there is still a long way to go until that target is reached. Therefore, the purpose of this study was to use molecular docking technique to identify new inhibitors for a novel antimalarial target with the overall aim of finding hit compounds which could be further optimized to become potential drug candidates. The docking protocol AutoDockVina was used alongside the molecular visualisation software UCSF Chimera to dock 100 naphthoquinones (labelled TM1-100) and 66 aryl diketones (labelled TM101-166) with the chosen target, Plasmodium vivax N-myristoyltransferase (PvNMT). Each docking session yielded the best 9 binding modes between the ligand and target. The hydrogen bond interactions of all binding modes were analysed, and the top six target molecules (TM) were short listed as the possible hit compounds (TM40, TM65, TM66, TM81, TM94 and TM165). These compounds displayed more than six hydrogen bonds under 3 angstroms over the 9 binding modes. Using Lipinski’s rule of 5, the potential hit compounds were further analysed to determine the drug-likeness and all were found to obey the parameters. Following the same method used to dock the ligands, twelve FDA approved antimalarial drugs were also docked with PvNMT for comparison purposes. Apart from proguanil, the other eleven antimalarial drugs displayed fewer hydrogen bonds under 3 angstroms over the 9 binding modes compared to all six of the potential hit compounds. This study discovered six compounds which displayed stronger interactions with the target protein compared to majority of the FDA approved drugs. The results of this investigation gave us new molecules that could be further investigated for the designing of novel drug-like compounds for the treatment of Malaria.