title: A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Meekyum Olivia
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Ferran
authors.initials: F
authors.lastname: Feixas
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Lindert
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bogue
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: William
authors.initials: W
authors.lastname: Sinko
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.|Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: César
authors.initials: C
authors.lastname: de Oliveira
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.|Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA.|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: James Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C039821:decaprenyl pyrophosphate synthetase; D051228:Geranyltranstransferase; C023266:undecaprenyl pyrophosphate synthetase
keywords: decaprenyl diphosphate synthase; docking; drug discovery; enzymatic mechanism; farnesyl diphosphate synthase; molecular dynamics; molecular modeling; prenyl synthase; tuberculosinyl adenosine synthase; tuberculosis