Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations.

Shohei Yamamoto,Pavel Karpov,Haruki Sogawa,Noriyuki Kurita,Ryosuke Saito,Sergey Shulga,Yaroslav Blume,Shunya Nakamura

doi:10.3390/antibiotics9120846

Abstract

The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of Mycobacteria. To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular simulations. We here employed protein–ligand docking, classical molecular mechanics (MM) optimizations, and ab initio fragment molecular orbital (FMO) calculations. Based on the specific interactions between FtsZ and the derivatives, as determined by FMO calculations, we proposed novel ligands, which can strongly bind to FtsZ and inhibit its aggregations. The introduction of a hydroxyl group into ZZ3 was found to enhance its binding affinity to FtsZ.

Highlights

Tuberculosis (TB) is one of the most widespread infectious diseases
In our previous molecular simulations [10,11], the specific interactions between filamentous temperature-sensitive Z (FtsZ) of Mtb and its inhibitors, the curcumin derivatives and Zantrins (Z3 and ZZ3), were investigated by molecular simulations, which were based on protein–ligand docking, classical molecular mechanics (MM), and ab initio fragment molecular orbital (FMO) calculations
In our previous study [11], the specific interactions between FtsZ and Zantrins Z3 and ZZ3 were investigated by molecular simulations

Summary

Introduction

Tuberculosis (TB) is one of the most widespread infectious diseases. It is caused by the bacillus. In our previous molecular simulations [10,11], the specific interactions between FtsZ of Mtb and its inhibitors, the curcumin derivatives and Zantrins (Z3 and ZZ3), were investigated by molecular simulations, which were based on protein–ligand docking, classical molecular mechanics (MM), and ab initio fragment molecular orbital (FMO) calculations. Z3 was previously synthesized and investigated by Margalit et al [7], while ZZ3 was developed based on Z3 [15] These Zantrins inhibited the activity of GTPase of FtsZ and prevented the generation of the Z-ring. To propose additional potent inhibitors of FtsZ aggregation, we prepared many types of derivatives based on ZZ3 (Figure 1a) and investigated their binding conformations in FtsZ of.

Proposal of Novel ZZ3 Derivatives as Potent Inhibitors of FtsZ

Binding Properties between FtsZ and the ZZ3 Derivatives by Replacing A-Part

Conclusions