Computational approaches: discovery of GTPase HRas as prospective drug target for 1,3-diazine scaffolds

Sanjiv Kumar,Siong Meng Lim,Vasudevan Mani,Balasubramanian Narasimhan,Syed Adnan Ali Shah,Kalavathy Ramasamy,Deepika Sharma

doi:10.1186/s13065-019-0613-8

Abstract

Heterocyclic 1,3-diazine nucleus is a valuable pharmacophore in the field of medicinal chemistry and exhibit a wide spectrum of biological activities. PharmMapper, a robust online tool used for establishing the target proteins based on reverse pharmacophore mapping. PharmMapper study is carried out to explore the pharmacological activity of 1,3-diazine derivatives using reverse docking program. PharmMapper, an open web server was used to recognize for all the feasible target proteins for the developed compounds through reverse pharmacophore mapping. The results were analyzed via molecular docking with maestro v11.5 (Schrodinger 2018-1) using GTPase HRas as possible target. The molecular docking studies displayed the binding behavior of 1,3-diazine within GTP binding pocket. From the docking study compounds s3 and s14 showed better docked score with anticancer potency against cancer cell line (HCT116). Hence, the GTPase HRas may be the possible target of 1,3-diazine derivatives for their anticancer activity where the retrieved information may be quite useful for developing rational drug designing. Furthermore the selected 1,3-diazine compounds were evaluated for their in vitro anticancer activity against murine macrophages cell line. 1,3-Diazine compounds exhibited good selectivity of the compounds towards the human colorectal carcinoma cell line instead of the murine macrophages. The toxicity study of the most active compounds was also performed on non cancerous HEK-293 cell line.

Highlights

Heterocyclic compounds play the vital role in pharmaceutical field due to their specific chemical reactivity and block the normal functioning of biological receptors
PharmMapper sets the feasible potential targets based on the reverse pharmacophore mapping of given 1,3-diazine compounds
In the GTPase HRas protein binding site, the further docking of 1,3-diazine compounds produced the docking poses of the most active compound and GTP used as positive control

Summary

Introduction

Heterocyclic compounds play the vital role in pharmaceutical field due to their specific chemical reactivity and block the normal functioning of biological receptors. Data set The data set of reported 1,3-diazine derivatives (s1–s16) have good anticancer activity against human colorectal carcinoma cancer cell line (HCT116) were selected from the earlier study for the establishment of the pharmacophore model. The molecular structures of the selected data set of 1,3-diazine derivatives and their anticancer screening results are shown in Table 3 [13]. Glide only modifies the ligand’s internal torsional coordinates during docking, so the remaining geometric parameters need to be optimized in advance They must each consist of a single molecule without covalent receptor bonds, with no accompanying fragments, such as counter ions and solvent molecules. Protein preparation The protein chosen for the molecular docking study of selected data set of 1,3-diazine derivatives, GTPase HRas (PDB Id: 2CL7) was obtained from the Protein Data Bank (Additional file 1). Using the Synergy/HTX MultiScan reader (BioTek) absorbance at 580 nm was registered and the lethal dose LD50 was calculated and the selectivity index (SI) calculated

Results and discussion

GTPase HRas

Conclusion