Targeting the dynamical differences in acetylcholinesterase from mosquito and non-target species for the development of new insecticides to combat malaria and dengue

Dnr:

SNIC 2017/1-296

Type:

SNAC Medium

Principal Investigator:

Anna Linusson

Affiliation:

Umeå universitet

Start Date:

2017-07-01

End Date:

2018-01-01

Primary Classification:

10405: Organisk kemi

Secondary Classification:

30103: Läkemedelskemi

Webpage:

http://www.chemistry.umu.se/forskning/group-leaders/anna-linusson/

Allocation

Abstract

We ask for 50% core hours at Beskow. Previously, we have submitted a 100% application for Kebnekaise at HPC2N, which is our historical HPC. The motivation for an application to Beskow is that we are experiencing major problem with running of jobs using Gromacs on HPC2N from last 3 months. The local support is working on it but still has no satisfying solution. Because of this, we are unable to make advancement in our research problem, which is why we submit an additional application. Our long-term research goal is to develop new insecticides targeting disease-transmitting mosquitoes [1]. Currently used insecticides are limited in scope due to toxicity and/or that the heavy usage of such causes resistant mosquito strains. Therefore, new selective inhibitors are urgently needed to combat disease-transmitting mosquitoes, and thus reduce mosquito-borne diseases like malaria and dengue. Common insecticides work by inhibiting the enzyme acetylcholinesterase (AChE), which leads to muscle paralysis and death. New ways to inhibit AChE in mosquitoes (mqAChE) have been proposed and designed using sequence and structural comparison between mosquito and vertebrate species [2]. Further, to overcome the carbamate insensitivity conferred by the G119S mutation in mqAChE1, new covalent inhibitors have been developed but they were poorly selective to mqAChE1 over human AChE [3]. Our recent study suggests that non-covalent inhibitors are less sensitive to G119S resistance mutation. It is noteworthy that examples of non-covalent inhibitors for mqAChE1 are very sparse. In a recent study by us, selective non-covalent inhibitors have been identified for mosquitoes using differential high throughput screening [4]. Also, the structure modeling of mqAChE1 suggested that the selectivity of both covalent and non-covalent inhibitors are related to the differences in two loops at the entrance of active site gorge of AChE. These studies are based on a single static structural model. However, proteins are dynamical in nature and amino acid sequence variations are known to be responsible for substrate selectivity. Therefore, comparative molecular dynamics (MD) simulations and advanced modeling techniques would be crucial to understand molecular mechanism of insecticide specificity in AChE from different species. In the present study, MD simulations of AChE from different mosquito and vertebrate species will be performed. The simulations will further analyzed to identify dynamics variations in the two loops and other regions near to active site gorge along with the interaction network both in apo and in presence of inhibitors identified by us. Based on these studies, novel selective non-covalent inhibitors with enhanced potency will be designed using both computational and experimental approach targeting mqAChE1 and G119S mutation. The research will have an impact on insecticide design and medicinal chemistry in general. References [1] Bhatt, S., et al. (2015). Nature 526: 207-211. [2] Pang, Y. P. (2006). PLoS One 1: e58. [3] Camerino, E., et al. (2015). Bioorg Med Chem Lett 25: 4405-4411. [4] Engdahl C., et al. (2016). J Med Chem. 59: 9409-9421