Non‐Bisphosphonate Inhibitors of Isoprenoid Biosynthesis Identified via Computer‐Aided Drug Design

Jacob D Durrant,Rong Cao,Eric Oldfield,Anna Sankovsky,J Andrew Mccammon,Wei Zhu,Alemayehu A Gorfe,Jikun Li

doi:10.1111/j.1747-0285.2011.01164.x

Abstract

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads.

Highlights

Two interesting new anti-infective targets involved in isoprenoid biosynthesis are farnesyl diphosphate synthase (FPPS) and undecaprenyl diphosphate synthase (UPPS) [18,19,20,21]
FPPS catalyzes the condensation of dimethylallyl diphosphate (DMAPP) with isopentenyl diphosphate (IPP) to form geranyl diphosphate (GPP) and thence, farnesyl diphosphate (FPP) [22], while UPPS elongates FPP via cis double-bond addition to produce undecaprenyl diphosphate (UPP) (Figure 1) [19]
Molecular dynamics (MD) simulations As the molecular motions of protein receptors play a critical role in ligand binding, we first studied FPPS dynamics before attempting to computationally identify non-bisphosphonate FPPS inhibitors

Summary

Introduction

FPPS catalyzes the condensation of dimethylallyl diphosphate (DMAPP) with isopentenyl diphosphate (IPP) to form geranyl diphosphate (GPP) and thence, farnesyl diphosphate (FPP) [22], while UPPS elongates FPP via cis double-bond addition to produce undecaprenyl diphosphate (UPP) (Figure 1) [19]. Both enzymes are essential for bacterial cell growth, and UPPS is of particular interest because it is absent in humans.

Methods

Results

Conclusion