A Molecular Dynamics Investigation of Mycobacterium Tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery

Chem Biol Drug Des. 2015 Jun;85(6):756-69. doi: 10.1111/cbdd.12463. Epub 2014 Nov 25.


With the rise in antibiotic resistance, there is interest in discovering new drugs active against new targets. Here, we investigate the dynamic structures of three isoprenoid synthases from Mycobacterium tuberculosis using molecular dynamics (MD) methods with a view to discovering new drug leads. Two of the enzymes, cis-farnesyl diphosphate synthase (cis-FPPS) and cis-decaprenyl diphosphate synthase (cis-DPPS), are involved in bacterial cell wall biosynthesis, while the third, tuberculosinyl adenosine synthase (Rv3378c), is involved in virulence factor formation. The MD results for these three enzymes were then compared with previous results on undecaprenyl diphosphate synthase (UPPS) by means of active site volume fluctuation and principal component analyses. In addition, an analysis of the binding of prenyl diphosphates to cis-FPPS, cis-DPPS, and UPPS utilizing the new MD results is reported. We also screened libraries of inhibitors against cis-DPPS, finding ~1 μm inhibitors, and used the receiver operating characteristic-area under the curve (ROC-AUC) method to test the predictive power of X-ray and MD-derived cis-DPPS receptors. We found that one compound with potent M. tuberculosis cell growth inhibition activity was an IC(50) ~0.5- to 20-μm inhibitor (depending on substrate) of cis-DPPS, a ~660-nm inhibitor of Rv3378c as well as a 4.8-μm inhibitor of cis-FPPS, opening up the possibility of multitarget inhibition involving both cell wall biosynthesis and virulence factor formation.

Keywords: decaprenyl diphosphate synthase; docking; drug discovery; enzymatic mechanism; farnesyl diphosphate synthase; molecular dynamics; molecular modeling; prenyl synthase; tuberculosinyl adenosine synthase; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Alkyl and Aryl Transferases / chemistry*
  • Alkyl and Aryl Transferases / metabolism
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Computer-Aided Design
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Geranyltranstransferase / antagonists & inhibitors
  • Geranyltranstransferase / chemistry*
  • Geranyltranstransferase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Mycobacterium tuberculosis / chemistry
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Enzyme Inhibitors
  • Alkyl and Aryl Transferases
  • decaprenyl pyrophosphate synthetase
  • Geranyltranstransferase
  • undecaprenyl pyrophosphate synthetase