BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//CERN//INDICO//EN
BEGIN:VEVENT
SUMMARY:Steroidal Pregnanes as 11β-HSD1 Modulators: Insights from Random 
 Forest-Based QSAR and Atomistic Simulations
DTSTART;VALUE=DATE-TIME:20260327T103000Z
DTEND;VALUE=DATE-TIME:20260327T105000Z
DTSTAMP;VALUE=DATE-TIME:20260426T093155Z
UID:indico-contribution-10309@events.saip.org.za
DESCRIPTION:Speakers: Oludare Ogunyemi (University of Ibadan)\nThe enzyme 
 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a validated therap
 eutic target for Type 2 diabetes mellitus due to its role in local regener
 ation of active glucocorticoids. Current inhibitors are often limited by t
 heir constrained chemical diversity\, moderate potency\, and off-target ef
 fects. The therapeutic potential of steroidal pregnanes in diabetes and me
 tabolic disorders is been widely reported\; however\, their molecular targ
 ets\, particularly in glucocorticoid signaling\, remain poorly understood.
  This study explored the interactions of a curated library of steroidal pr
 egnanes with 11β-HSD1 using integrated Machine Learning (ML)-based QSAR\,
  molecular docking\, 100 ns Molecular Dynamics (MD) simulations\, and MM-G
 BSA binding free energy calculations. Initial exploratory chemical space a
 nalysis of the IC50 bioactivity dataset revealed that hydrogen donors\, mo
 lecular weight\, and lipophilicity may contribute to the bioactivity of 11
 β-HSD1 inhibitors. Evaluation of 42 ML algorithms based on performance me
 trics revealed Random Forest Regressor (RFR) as a top model for bioactivit
 y predictions.  Molecular docking simulation of the top RFR-predicted comp
 ounds (pIC50 ≥ 6.0 and pKi ≥ 7.8) with the active site of 11β-HSD1 id
 entified three compounds (pregnane-3\, 20-diol disulphate (P1)\, 20-Piperi
 din-2-yl-5α-pregnan-3β\,20-diol (P2)\, and 12\,20-di-O-benzoyl-pregnane-
 3β\,12β\,14β\,20-tetraol (P3)). While the reference carbenoxolone prima
 rily strongly involved peripheral polar contacts to stabilize its orientat
 ion\, the pregnane scaffolds demonstrated deeper insertion into the hydrop
 hobic catalytic cavity of 11β-HSD1\, resulting in enhanced shape compleme
 ntarity and van der Waals packing. The thermodynamic parameters computed f
 rom the MD simulation trajectories revealed both the structural stability 
 and intrinsic conformational flexibility of the 11β-HSD1–pregnane compl
 exes. Moreover\, the lower MM-GBSA binding energies of P1 (-43.58 kcal/mol
 ) and P3 (-44.95 kcal/mol) as compared with the reference carbenoxolone (-
 24.19 kcal/mol) indicate high binding affinity and validate the docking sc
 ores of the hits. Additionally\, the leads exhibited favorable physicochem
 ical and pharmacokinetic profiles. Overall\, our findings provide mechanis
 tic insights into ligand binding and highlight key structural features tha
 t may account for 11β-HSD1 modulation by steroidal pregnanes\, offering a
  framework for the rational design of pregnane-derived therapeutics.\n\nht
 tps://events.saip.org.za/event/272/contributions/10309/
LOCATION:
URL:https://events.saip.org.za/event/272/contributions/10309/
END:VEVENT
END:VCALENDAR