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Computational elucidation of novel antagonists and binding insights by structural and functional analyses of serine hydroxymethyltransferase and interaction with inhibitors

Authors :
Roshan Kamal Topno
Manas Ranjan Dikhit
Pradeep Das
Sahil Sinha
Vahab Ali
Jyoti Prava Majhee
Yousuf Ansari
Ganesh Chandra Sahoo
Source :
Gene Reports. 10:17-25
Publication Year :
2018
Publisher :
Elsevier BV, 2018.

Abstract

The crystallographic structure of the Leishmania donovani serine hydroxymethyltransferase ( Ld SHMT), an attractive target for the design of leishmanicidal agents, is still unknown. Serine hydroxymethyltranferase (SHMT) is a key enzyme in the purine biosynthesis pathway, which is essential for the synthesis of DNA in leishmania parasite. Aim of this study is to find out the novel drug candidate against this parasitic protozoan. The present study describes the development of a robust homology model of Ld SHMT to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Here we report a robust three-dimensional structure (98.4% of the residues were in the most favored region and additional allowed region) which consist of N terminal small domain (residues 1–46), N terminal large domain (residues 46–298) and C terminal domain (residues 299–457). The second N-terminal domain or the large domain (residues 46–298) binds PLP, has most of the active site residues and folds into α–β–α type sandwich containing eight α-helices wrapped around seven mixed β-sheets and third is the C-terminal domain (residues 299–457) folds into an α–β sandwich. Docking studies of diverse reported structures with modeled protein exhibited good binding affinities. Purvalanol, revealed a good binding affinity (− 29.78) and residues involved in interaction are ASP208, Arg243, His236 and Lys237 forming hydrogen bonds, which signifies the presence of strong interaction with the target protein. Methotrexate-alpha-arginine and fluoresceinated have also exhibited good binding affinity − 38.85 and − 37.27 respectively. Pemetrexed, which has been earlier implicated in treatment of lung cancer, also exhibited a good binding affinity (− 32.76).The residues which played a crucial role in the formation of strong H bonds are Ser102, Gly101, Arg243, Lys360, Asn361 and Lys 237. Apart from these molecules, several other molecules also showed strong interaction with Ld SHMT. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development.

Details

ISSN :
24520144
Volume :
10
Database :
OpenAIRE
Journal :
Gene Reports
Accession number :
edsair.doi...........43139235b1b7288892c5e027b0d340e1
Full Text :
https://doi.org/10.1016/j.genrep.2017.10.010