An Insilico approach to design the mutated 3D structure of BCHE using AB initio method and testing the efficacy of the selected ligands in inhibiting the S226G mutation

Author Name: Allam Apparao,Gundlapally Jyothsna,Pulipati Shalini,*Amit Kumar
Author Email: amit.kumar@dnares.in

Abstract

Butyryl cholinesterase (BCHE) is a protein belonging to ester lipase super family. It hydrolyzes choline esters in addition to its role in nerve impulse transmission. BCHE has three active sites located at 226, 353 and 456 which are responsible for acyl ester intermediate, and charge relay system. Among the three sites, 226 (serine) have been reported to have the natural variant S 226 G. Alteration at this site affects the functionality of the protein due to its importance in the active site formation. Variations in this gene have also been reported in BCHE deficient conditions. BCHE is implicated to have a role in lipid metabolism; any alteration to its function causes a hindrance to the mobilization of fats leading to obesity which causes Type II Diabetes. Present work involves complete analysis of BCHE gene with reference to the site S226G and designing the mutated BCHE structure using AB Initio approach. Docking studies were performed with potent lead molecules with an aim to inhibit or minimize the adverse effect of the mutation.

Keywords

BCHE, Docking, Mutation, Obesity, Lipid Metabolism, Type II Diabetes.

Introduction

Diabetes has become one of the most common diseases among the people of all age groups. Type 2 diabetes also known as “Non insulin dependent diabetes mellitus” is characterized by a defect in the insulin activity. It is caused due to the impairment in the insulin signaling mechanism, as a consequence of insulin resistance. Large number of proteins has been reported to be involved in the onset of diabetes; BCHE is one such protein, whose exact role on the onset of the condition is still an enigma. Cholinesterases are a class of proteins involved in the hydrolysis of cholines. The two cholinesterases, ACHE and BCHE though belong to the same class they differ in their substrate requirement. ACHE is specific to acetylcholine as its substrate, whereas BCHE is called non-specific esterase or pseudo cholinesterase as it do not show substrate specificity, it hydrolyses wide range of esters, especially the depolarizing neuromuscular blocking agent succinylcholine. ACHE and BCHE both belong to a super family “Ester Lipases” [1] which indicates that apart from their esterase activity they are also involved in lipid metabolism. This can be considered for their role in Obesity.
BCHE is a protein of 602 amino acids in length located on the q arm of the 3rd chromosome. It belongs to the family of alpha beta hydrolases [2] based upon the structural motifs present in it. It is known to play a vital role in Diabetes, Adiposity and Nerve disorders [3]. In vertebrates, it appears in the serum, hemopoietic cells, liver, lung and heart, at cholinergic synapses and in the central nervous system [4]. The mutations in BCHE are known to have various effects in the normal metabolism of the body. BCHE is reported to have a role in insulin resistance [5], one of the causes for the onset of Diabetes. It also has a role in most of the neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease.

Conclusion

From the above work it was studied that BCHE is one of the major protein that is involved in insulin resistance thereby being indispensable in diabetic study. One of the domains of BCHE is common to two other proteins, ACHE and HSL which implies their functional similarity reporting its role in lipid metabolism. S226G mutation of the protein is one of the mutational hot spot lying in the active site which has been considered as the target in this work .The compounds that can be used as suitable drug candidates have been selected and subjected for various screening procedures. The final ligands used for docking were 1-(((2-((5-cyanopyridin-2-yl) amino) ethyl) amino) acetyl)-2-cyano-(s)-pyrrolidine, N-alanylproline-o-(4-nitrobenzoyl) hydroxylamine, Saxagliptin, 1-(((3-hydroxy-1-adamentyl) amino) acetyl-2 cyanopyrrolidine, Vildagliptin, Diprotin and Topiramate. All the ligands were optimized using suitable software. Docking was performed in Molegro and GOLD softwares to select the best compound that can be used as a drug against BCHE. From the docking result analysis it was found that the compound named “N-alanylproline-o-(4-nitrobenzoyl) hydroxylamine is the best drug candidate due to its minimum Moldock score and maximum fitness value of it when compared to the other ligands.
To prove the efficiency of the selected ligand in treating the adverse symptoms of diabetes the work can be extended to clinical trials. This can be one of the approaches for the treatment of Diabetes.

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