Study on Binding Energies of Betulinic Acid from G. boveanum and some Designed (4-chlorophenyl)betulinic Acid Derivatives as Potential Inhibitors of Plasmodium Lactate Dehydrogenase (pLDH)

Ahmed Jibrin Uttu; Abdulrazaq  Tukur; Mark Madumelu; Rukayya Muhammed Obansa; Zakari Ya’u Ibrahim; Abduljelil Ajala; Adawara Ndaghiya Samuel

doi:10.5455/JPPR.20250420063433

Abstract
Aim/Background: Malaria is a widespread infectious disease that continues to be a major source of morbidity and death in both developed and underdeveloped countries. Plasmodium falciparum is known to causes the most lethal strain of malaria and contributes to 90% of all malaria deaths. Antimalarial drugs often target lactate dehydrogenase, a crucial protein in Plasmodium that is necessary for treating malarial infections.
Methods: ChemDraw was used to design ten (10) Betulinic acid derivatives. Computational technique was used to study the interactions of betulinic acid from Glossonema boveanum and the novel (4-chlorophenyl)betulinic acid derivatives with the crystal structure of Plasmodium lactate dehydrogenase (pLDH, PDB: 2A94). The docking study on the compounds with PDB 2A94 using the mCule online server while ADMET prediction online tool (SwissADME and pkCSM) were used for evaluation of the pharmacokinetics and druglikeness properties.
Results: Computational technique was used to study the interactions of betulinic acid from Glossonema boveanum and 10 novel (4-chlorophenyl)betulinic acid derivatives with the crystal structure of Plasmodium lactate dehydrogenase (pLDH, PDB: 2A94). The docking study on the compounds with PDB 2A94 using the mCule online server had binding energies which ranged between − 4.50 and − 8.20 kcal/mol, in comparison to the control drug which had binding energy of − 7.4 kcal/mol. However, compounds 8 and 9 had binding energies of − 7.90 and − 8.20 kcal/mol, respectively, outperforming the control drug. The ADMET analysis results showed that the deigned compounds 8 and 9 had promising drug-like properties, including strong inhibitory effects, good pharmacokinetics, and no toxicity issues.
Conclusion: Compounds 8 and 9 from the designed compounds could be helpful in the development of more potent antimalarial drugs as well as a suitable replacement for those already commercially available.

Key words: Glossonema boveanum; Plasmodium; Betulinic acid; Malaria; Binding affinities