Computational Evaluation of Indole Alkaloids from Rauwolfia vomitoria as Potential Anticancer Agents: Molecular Docking and ADME Profiling

Abstract

Background: Cancer continues to pose a major global health challenge, particularly in low- and middle-income countries, where treatment costs and accessibility remain limiting. Natural products such as Rauwolfia vomitoria have shown significant promise as alternative sources of bioactive anticancer compounds. This study evaluated the anticancer potential of two key indole alkaloids—Ajmalicine and Alstonine—through molecular docking and in silico pharmacokinetic and toxicity profiling. Methods: A computational approach was employed using Schrödinger Maestro Suite (2023-3) for docking simulations, SwissADME for ADMET analysis, and ProTox-III for toxicity prediction. Six cancer-associated targets—BCL-2, PI3K, EGFR, STAT3, HDAC, and NF-κB—were selected to compare binding affinities and drug-likeness properties of the alkaloids against known inhibitors. Results: Both compounds exhibited favorable pharmacokinetic profiles with high gastrointestinal absorption and good drug-likeness scores. Alstonine demonstrated superior binding affinities against BCL-2 (–5.042 kcal/mol), PI3K (–6.017 kcal/mol), and STAT3 (–5.877 kcal/mol), comparable to known inhibitors such as Lisaftoclax and Napabucasin. Hydrogen bonding analysis revealed strong, short-range interactions (<2.0 Å) contributing to binding stability. Toxicity predictions classified both alkaloids as Class 3 (LD₅₀ = 215–300 mg/kg), indicating moderate toxicity that warrants optimization. ADME predictions revealed good oral bioavailability, high gastrointestinal absorption, and blood–brain barrier permeability. Conclusion: Alstonine displayed the most promising anticancer potential, with favorable pharmacokinetic properties and multi-target binding profiles. These findings highlight the potential of Rauwolfia vomitoria alkaloids as lead scaffolds for anticancer drug development. Experimental validation and structural refinement are recommended to advance these compounds toward clinical applicability.