Structural and functional characterization of 6-phosphogluconate dehydrogenase in Plasmodium falciparum (3D7) and identification of its potent inhibitors

AbstractThe malarial parasite Plasmodium falciparum predominantly causes severe malaria and deaths worldwide. Moreover, resistance developed by P. falciparum to frontline drugs in recent years has markedly increased malaria-related deaths in South Asian Countries. Ribulose 5-phosphate and NADPH synthesized by Pentose Phosphate Pathway (PPP) act as a direct precursor for nucleotide synthesis and P. falciparum survival during oxidative challenges in the intra-erythrocytic growth phase . In the present study, we have elucidated the structure and functional characteristics of 6-phosphogluconate dehydrogenase (6PGD) in P. falciparum and have identified potent hits against 6PGD by pharmacophore-based virtual screening with ZINC and ChemBridge databases. Molecular docking and Molecular dynamics simulation, binding free energies (MMGBSA & MMPBSA), and Density Functional Theory (DFT) calculations were integratively employed to validate and prioritize the most potential hits. The 6PGD structure was found to have an open and closed conformation during MD simulation. The apo form of 6PGD was found to be in closed conformation, while a open conformation attributed to facilitating binding of cofactor. It was also inferred from the conformational analysis that the small domain of 6PGD has a high influence in altering the conformation that may aid in open/closed conformation of 6PGD. The top three hits identified using pharmacophore hypotheses were ChemBridge_11084819, ChemBridge_80178394, and ChemBridge_17912340. Though all three hits scored a high glide score, MMGBSA, and favorable ADMET properties, ChemBridge_11084819 and ChemBrdige_17912340 showed higher stability and binding free energy. Moreover, these hits also featured stable H-bond interactions with the active loop of 6PGD with binding free energy comparable to substrate-bound complex. Therefore, the ChemBridge_11084819 and ChemBridge_17912340 moieties demonstrate to have high therapeutic potential against 6PGD in P. falciparum.Communicated by Ramaswamy H. SarmaKeywords: Plasmodium falciparum6-phosphogluconate dehydrogenase (6PGD)molecular dynamics simulationspharmacophore-based virtual screeningMMGBSA Disclosure statementNo conflict of interest was reported by the authors.Correction StatementThis article has been corrected with minor changes. These changes do not impact the academic content of the article.Additional informationFundingJJ thanks the DST INDO-TAIWAN (GITA/DST/TWN/P-86/2019), Department of Biotechnology-Bioinformatics Centre (BIC)-No.BT/PR40154/BTIS/137/34/2021, TANSCHE (RGP/2019-20/ALU/HECP-0049 dated:27/04/2021), DBT-NNP-N0.BT/PR40156/BTIS/137/54/2023, DST-Fund for Improvement of S&T Infrastructure in Universities & Higher Educational Institutions (FIST) (SR/FST/LSI-667/2016) (C), and DST-Promotion of University Research and Scientific Excellence (PURSE phase II) (No. SR/PURSE Phase 2/38 (G), 2017) for the financial support and facilities. CJ Chen greatly acknowledges MOST 107-2923-B-213-001-MY3 and MOST 108-2311-B-213-001-MY3 for providing financial assistance through Major Research Projects. NH greatly acknowledges the Department of Science and Technology (DST), for providing financial assistance through DST/INSPIRE Fellowship/2019/IF190083. The authors thank Vision Research Foundation, Chennai for providing a computational facility. AM, sincerely thank ICMR – Senior Research Fellowship (107/2022-ECD-II dated 01/11/22) for providing financial assistance.