Ligand based virtual screening to find novel inhibitors against plant toxin Ricin by using the ZINC database.

Vinita Mishra,C V S Siva Prasad

doi:10.6026/97320630007046

Abstract

Ricin is known as a potent toxin against animals. It consists of two chains, Ricin Toxin A (RTA) and Ricin Toxin B (RTB). The toxic effect is known to be caused by RTA. Inhibitors for RTA with less efficiency have been reported. Hence, it is of interest to identify new inhibitors. Virtual screening methods (computer aided drug designing) to find similar molecules in drug database were used for screening new inhibitors against RTA. We used the structure of RTA in complex with Pteroic acid (PDB code: 1BR6) as target molecule. Ligand based virtual screening approach was used in which the known inhibitory molecule Pteroic acid (PTA) served as a template to identify similar ligands from the ZINC database. These ligands were docked inside the binding pocket of RTA by using the MVD (Molegro Virtual Docker). This approach successfully identified six novel compounds. These docked ligands interacted with Asn78, Ala79, Val81, Gly121 and Ser176 amino acids, which are key residues of the RTA active site. Three compounds in particular, ZINC05156321 (6, 7 diphenylpteridin-4-ol), ZINC05156324 (6, 7-bis (3-fluorophenyl) pteridin-4-ol) and ZINC08555900 (6, 7-bis (4-fluorophenyl)-1H-pteridin-4-one), showed higher binding affinity in comparison to PTA, with high interaction energy, better space fitting and electrostatic interactions. These molecules should be tested for in vitro and in vivo activities in future for consideration as effective inhibitors.

Highlights

The tertiary (30) structure of Ricin is a globular and glycosylated heterodimer, with an approximate molecular weight of 60-65 kDa (Figure 1) [1]. It consists of two chains namely Ricin Toxin A Chain (RTA) and Ricin Toxin B Chain (RTB)
Active site consists of following amino acid residues ASN78, TYR 80, VAL81, PHE93, GLY121, ASN122, TYR123, ARG134, ILE172, GLU177, ARG180, GLU208, ASN209 and TRP211 [10]
Results from earlier investigators had represented that active site of Ricin Toxin-A chain (RTA) has been complexed with ligand Pteroic acid (PTA) (Figure 1b)

Summary

Introduction

The tertiary (30) structure of Ricin is a globular and glycosylated heterodimer, with an approximate molecular weight of 60-65 kDa (Figure 1) [1]. It consists of two chains namely Ricin Toxin A Chain (RTA) and Ricin Toxin B Chain (RTB). Ricin A Chain (Figure 1) is an N-glycoside hydrolase made up of 267 amino acids [2]. It has three structural domains in which approximately 50% of the polypeptides are arranged into αhelices and β-sheets [3]. RTA targets adenine at position 4324 (A4324) of the highly conserved sequence, which is about 12 nucleotides long and universally

Methods

Results

Conclusion