Identification of potential inhibitor and enzyme-inhibitor complex on trypanothione reductase to control Chagas disease. (December 2016)

• Record Type: Journal Article
• Authors: Hossain, Mohammad Uzzal; Oany, Arafat Rahman; Ahmad, Shah Adil Ishtiyaq; Hasan, Md. Anayet; Khan, Md. Arif; Siddikey, Md Al Ahad
• Is Part Of: Computational biology and chemistry. Volume 65(2016)
• Page Start: 29
• Page End: 36
• Publication Date: 2016-12
• Subjects: Chagas disease -- Pharmacoinformatics -- Molecular docking -- Enzyme-inhibitor complex; TryR trypanothione reductase -- T. cruzi Trypanosoma cruzi -- QUM quinacrine mustard -- ADMET absorption, distribution, metabolism distribution and toxicity -- BBB blood brain barrier transport -- LogBB Blood Brain Distribution -- LogPS blood brain barrier permeability -- DBP Drug binding to plasma protein -- Vd volume of distribution -- Pgp P-glycoprotein -- QSAR quantititive structure–activity relationship -- LogS solubility -- TPSA the polar surface area -- cLogP logarithm of partition coefficient -- Mw molecular weight; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2016.10.002
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Abstract: Chagas is a parasitic disease with major threat to public health due to its resistance against commonly available drugs. Trypanothione reductase (TryR) is the key enzyme to develop this disease. Though this enzyme is well thought-out as potential drug target, the accurate structure of enzyme-inhibitor complex is required to design a potential inhibitor which is less available for TryR. In this research, we aimed to investigate the advanced drug over the available existing drugs by designing inhibitors as well as to identify a new enzyme-inhibitor complex that may act as a template for drug design. A set of analogues were designed from a known inhibitor Quinacrine Mustard (QUM) to identify the effective inhibitor against this enzyme. Further, the pharmacoinformatics elucidation and structural properties of designed inhibitor proposed effective drug candidates against Chagas disease. Molecular docking study suggests that a designed inhibitor has higher binding affinity in both crystal and modeled TryR and also poses similar interacting residues as of crystal TryR-QUM complex structure. The comparative studies based on in silico prediction proposed an enzyme-inhibitor complex which could be effective to control the disease activity. So our in silico analysis based on TryR built model, Pharmacophore and docking analysis might play an important role for the development of novel therapy for Chagas disease. But both animal model experiments and clinical trials must be done to confirm the efficacy of the therapy.