Abstract
Chirality is a common phenomenon, and it is meaningful to explore interactions between stereoselective bio-macromolecules and chiral small molecules with preclinical and clinical significance. Protopanaxadiol-type ginsenosides are main effective ingredients in ginseng and are prone to biotransformation into a pair of ocotillol C20-24 epoxide epimers, namely, (20S,24S)-epoxy-dammarane-3,12,25-triol (24S-PDQ) and (20S,24R)-epoxy dammarane-3,12,25-triol (24R-PDQ) that display stereoselective fate in vivo. However, possible molecular mechanisms involved are still unclear. The present study aimed to investigate stereoselective ADME (absorption, distribution, metabolism and excretion) characteristics of PDQ epimers based on molecular docking analysis of their interaction with some vital proteins responsible for drug disposal. Homology modeling was performed to obtain 3D-structure of the human isoenzyme UGT1A8, while calculation of docking score and binding free energy and ligand–protein interaction pattern analysis were achieved by using the Schrödinger package. Stereoselective interaction was found for both UGT1A8 and CYP3A4, demonstrating that 24S-PDQ was more susceptible to glucuronidation, whereas 24R-PDQ was more prone to oxidation catalyzed by CYP3A4. However, both epimers displayed similarly strong interaction with P-gp, a protein with energy-dependent drug-pump function, suggesting an effect of the dammarane skeleton but not C-24 stereo-configuration. These findings provide an insight into stereo-selectivity of ginsenosides, as well as a support the rational development of ginseng products.
Highlights
Natural biomolecules with rich diversity in chemical structure are important resources for modern drug discovery [1]
Ginsenoside is a class of triterpenoid saponins abundant in ginseng that has been reputed as the king of medicinal herbs and used as a tonic, prophylactic and restorative agent in traditional medicine for thousands of years [2]
For the target proteins P-gp and CYP3A4 that have known crystal structures of protein-ligand complexes collected in Protein Data Bank (PDB), the 3-D structures with high resolution and good ligand similarity to the small molecules were selected for further docking
Summary
Natural biomolecules with rich diversity in chemical structure are important resources for modern drug discovery [1]. The difference in spatial orientation of C-20 hydroxyl further yields a pair of epimers for each, and those in fresh ginseng are usually of the 20S-configuration, while processed ginseng products, such as red ginseng, contain both 20R- and 20S-epimeric forms [6,7]. Bhioymdorleocxulyesl 2f0u2r0t,h1e0,r1y12ields a pair of epimers for each, and those in fresh ginseng are usually of the2 2of01S2-. Configuration, while processed ginseng products, such as red ginseng, contain both 20R- and 20S-. TThhee ddiiffffeerreenntt sstteerreeoocchheemmiissttrryy ooff PPDDQQ eeppiimmeerrss lleeaaddss ttoo ssiiggnniifificcaanntt sstteerreeoosseelleeccttiivviittiieess iinn bbootthh pphhaarrmmaaccoollooggiiccaall eeffffeeccttss aanndd AADDMMEE pprrooppeerrttiieess. OOuurr pprreesseenntt wwoorrkk aaiimmeedd ttoo iinnvveessttiiggaattee ppoossssiibbllee mmeecchhaanniissmmss iinnvvoollvveedd iinn sstteerreeoosseelleeccttiivvee AADDMMEE pprrooppeerrttiieess ooff PPDDQQeeppiimmeerrssbbyymmoolelceuculalrardodcokciknign,gw, hwichhichhahsabseebneednemdeomnsotnrastterdataesdaansinanvailnuvaabllueatboloel tionolstirnuscttruurcatlumraol lmecoulelacrulbairobloioglyogayndancdocmopmupteurt-ears-saissstiesdteddrdurgugddeseisgingntotopprreeddiicctt tthhee pprreeddoommiinnaanntt lliiggaanndd––pprrootteeiinn bbiinnddiinnggmmooddeessfofrorvivrtiurtaulaslcrsecerneiennginogn olanrglearlgiberalirbiersaroifescoomf pcooumnpdosuannddsexaancdt tehxraecettdhirmeee-ndsiimoneanlsio(3n-aDl)(3s-tDru) cstturruecstuorefs porfopteriontsein[1s6[]1. OOuurr pprreesseenntt wwoorrkk aaiimmeedd ttoo iinnvveessttiiggaattee ppoossssiibbllee mmeecchhaanniissmmss iinnvvoollvveedd iinn sstteerreeoosseelleeccttiivvee AADDMMEE pprrooppeerrttiieess ooff PPDDQQeeppiimmeerrssbbyymmoolelceuculalrardodcokciknign,gw, hwichhichhahsabseebneednemdeomnsotnrastterdataesdaansinanvailnuvaabllueatboloel tionolstirnuscttruurcatlumraol lmecoulelacrulbairobloioglyogayndancdocmopmupteurt-ears-saissstiesdteddrdurgugddeseisgingntotopprreeddiicctt tthhee pprreeddoommiinnaanntt lliiggaanndd––pprrootteeiinn bbiinnddiinnggmmooddeessfofrorvivrtiurtaulaslcrsecerneiennginogn olanrglearlgiberalirbiersaroifescoomf pcooumnpdosuannddsexaancdt tehxraecettdhirmeee-ndsiimoneanlsio(3n-aDl)(3s-tDru) cstturruecstuorefs porfopteriontsein[1s6[]1. 6T].heThfeinfidnindginsgws wouoludldgigvievessoommee iinnssiigghhttss iinnttoo sstteerreeoosseelleeccttiivvee bbiioollooggiiccaall eeffffeeccttss ooff tthheessee eeppiimmeerriicc iinntteerrmmeeddiiaattee mmeettaabboolliitteess ooff nnaattuurraallllyy aabbuunnddaanntt ggiinnsseennoossiiddeessanandd, t,htuhsu, sh,elhpeltpo bteottberetutenrdeurnstdaenrdstpanotdenptioatlemnteiachl amniescmhasnreissmposnrseibslpeofnosricbllienifcoarl ecffilincaiccayl aenffdicsaacfyetaynodfsgaifnesteynogf pgrinosdeuncgtsp. roducts
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