Computational evaluation of indole alkaloids as inhibitors of 3-hydroxykynurenine transaminase in malaria vector control.

The enzyme 3-hydroxykynurenine transaminase (3-HKT) is critical for the production of xanthurenic acid, a key metabolite required for Plasmodium falciparum gametogenesis in Anopheles mosquitoes. Recognizing the importance of disrupting this pathway, the study explores the potential of indole alkaloids as inhibitors of 3-HKT, leveraging their natural insecticidal properties. Computational methods, including virtual screening, molecular dynamics, and MMPBSA analyses, were applied to evaluate the binding affinity and stability of indole alkaloids. Virtual screening results revealed spiroindolone (EP4), asperpenazine (SP4), and strychnine (ST6) as the most promising inhibitors with the strongest binding free energy of -7.38, -7.21 and -7.12 kcal/mol for 3-HKT (PDB ID:2CH1) and -7.47 -7.13, and -7.08 kcal/mol for 2CH2, respectively. ST6 forms a structurally stable complex, but its interactions are energetically weaker, resulting in a lower binding affinity than EP4. The Molecular dynamics simulation study evaluated the stability and binding properties of EP4, SP4, and ST6 against 3-HKT using RMSD, RMSF, and ROG analyses, along with MM/PBSA calculations. The results showed that the EP4, ST6, and SP4 systems exhibited good stability and binding properties, with average RMSF values of 0.3 Å in all systems. The MMPBSA results supported MD results; EP4 demonstrated high binding energy of -69.658 and -77.025, followed by SP4 (-68.658 and -75.947), while ST6 exhibited binding energy values of -49.294 and -39.859 kJ/mol. The results revealed that EP4 and SP4 exhibited stable binding with the 3-HKT and could be suggestive candidates for anti-mosquito insecticide design. ST6 forms a stable complex, but the nature of the interactions (primarily van der Waals, less favorable electrostatics/solvation) makes it inferior to EP4, and thus optimization is vital. Further in vitro and in vivo studies should be conducted to validate the compounds' efficacy.