Docking-based preliminary study on the interactions of bile acids with drugs at the transporter level in intestinal bacteria.

OBJECTIVE The aim of this study was to estimate the binding-affinities of different bile acids towards drug transporters in Lactobacillus acidophilus and Bifidobacterium longum in order to predict the influence of bile acids and probiotics interactions on drug pharmacokinetics. MATERIALS AND METHODS In order to study interactions of bile acids with transporters of intestinal bacteria, molecular-docking step was performed, using SwissDock web-service. For the purpose of comparison, two natural bile acids, cholic acid (CA) and deoxycholic acid (DCA), and one semi-synthetic bile acid, 12-monoketocholic acid (MKC), were studied in parallel. The free-binding energy was used as the main criterion for ranking ligands. RESULTS Studied bile acids exhibited different binding affinities towards bacterial transporters with MKC showing the most prominent effect. For the majority of studied transporters, the estimated affinities of bile acids decreased in the following order: MKC-CA-DCA. Namely, 38.7% of examined transport proteins gave the lowest free-binding energy with MKC. The weak inverse relationship between number of hydrogen bonds and estimated free-binding energies was revealed. CONCLUSIONS The predominant effect of MKC for the majority of studied transport proteins suggests that keto group at carbon 12 of the steroid core has a significant influence on the properties of MKC and consequently, on interactions with membrane transporters. Present findings might have a role in the prediction of potential influence of bile acids and probiotics on drug pharmacokinetics.

[1]  K. Nikolić,et al.  The influence of bile salts on the distribution of simvastatin in the octanol/buffer system , 2016, Drug development and industrial pharmacy.

[2]  N. Pavlović,et al.  Application of bile acids in drug formulation and delivery , 2013 .

[3]  Shihab Hasan,et al.  Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera’s key metabolite Withaferin A , 2013, In Silico Pharmacology.

[4]  H. Al‐Salami,et al.  Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat , 2013, Journal of diabetes research.

[5]  M. Raffatellu,et al.  Probiotics: properties, examples, and specific applications. , 2013, Cold Spring Harbor perspectives in medicine.

[6]  Ryan G. Coleman,et al.  ZINC: A Free Tool to Discover Chemistry for Biology , 2012, J. Chem. Inf. Model..

[7]  M. Varma,et al.  Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability , 2012 .

[8]  Aurélien Grosdidier,et al.  SwissDock, a protein-small molecule docking web service based on EADock DSS , 2011, Nucleic Acids Res..

[9]  I. Tucker,et al.  Effect of bile salts on the transport of morphine-6-glucuronide in rat brain endothelial cells. , 2011, Journal of pharmaceutical sciences.

[10]  H. Gwak,et al.  Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats , 2011, Drug delivery.

[11]  Yang Zhang,et al.  I-TASSER: a unified platform for automated protein structure and function prediction , 2010, Nature Protocols.

[12]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[13]  Ian D Wilson,et al.  Drugs, bugs, and personalized medicine: Pharmacometabonomics enters the ring , 2009, Proceedings of the National Academy of Sciences.

[14]  J. Marin,et al.  Bile acids: chemistry, physiology, and pathophysiology. , 2009, World journal of gastroenterology.

[15]  Abdul W Basit,et al.  The gastrointestinal microbiota as a site for the biotransformation of drugs. , 2008, International journal of pharmaceutics.

[16]  I. Tucker,et al.  Influence of the semisynthetic bile acid (MKC) on the ileal permeation of gliclazide in healthy and diabetic rats. , 2008, Pharmacological reports : PR.

[17]  A. Friedler.  Bile Acids: chemistry, biosynthesis, analysis, chemical and metabolic transformations and pharmacology , 2008 .

[18]  Aurélien Grosdidier,et al.  EADock: Docking of small molecules into protein active sites with a multiobjective evolutionary optimization , 2007, Proteins.

[19]  M. Mikov,et al.  Structure and origin of bile acids: An overview , 2006, European Journal of Drug Metabolism and Pharmacokinetics.

[20]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[21]  P Augustijns,et al.  Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers. , 2004, International journal of pharmaceutics.

[22]  M. Putman,et al.  Molecular Properties of Bacterial Multidrug Transporters , 2000, Microbiology and Molecular Biology Reviews.

[23]  M. Mikov.  The metabolism of drugs by the gut flora , 1994, European Journal of Drug Metabolism and Pharmacokinetics.

[24]  R. Mazzanti,et al.  Bile acid inhibition of P‐glycoprotein–mediated transport in multidrug‐resistant cells and rat liver canalicular membrane vesicles , 1994, Hepatology.

[25]  M. Mikov,et al.  The Influence of Intestinal Tract and Probiotics on the Fate of Orally Administered Drugs. , 2014, Current issues in molecular biology.

[26]  M. Mikov,et al.  Probiotics as a Promising Treatment for Inflammatory Bowel Disease , 2014 .

[27]  I. Tucker,et al.  Mechanistic studies of the effect of bile salts on rhodamine 123 uptake into RBE4 cells. , 2012, Molecular pharmaceutics.

[28]  Hiroshi Nikaido,et al.  Efflux-Mediated Drug Resistance in Bacteria , 2012, Drugs.

[29]  M. Mikov,et al.  Cefotaxime pharmacokinetics after oral application in the form of 3α,7α-dihydroxy-12-keto-5β-cholanate microvesicles in rat , 2010, European Journal of Drug Metabolism and Pharmacokinetics.

[30]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.