Comparative Structural and Functional Analysis of Plasmodium Type II Nicotinamide Adenine Dinucleotide: Quinone...

Type II NADH: Quinone oxidoreductase (NDH2) represents a critical metabolic target in Plasmodium parasites. Although NDH2 lacks a direct human isoenzyme, it shares significant structural homology with human Apoptosis-Inducing Factor Mitochondrion-associated 1 (AIF-M1), presenting a substantial challenge for selective drug design. To address this selectivity hurdle, the first comparative computational study was conducted across five human-infecting Plasmodium species (P. falciparum, P. knowlesi, P. malariae, P. ovale, and P. vivax) using a natural compound library.

Homology models were constructed for understudied Plasmodium orthologs. The virtual screening of the South African Natural Compounds Database (SANCDB) was performed against Plasmodium NDH2, followed by Molecular Dynamics (MD) simulations to evaluate binding stability and cross-reactivity with human AIF-M1.

Compounds SANC00101, SANC00344, and SANC00418 demonstrated strong binding affinities to PfNDH2 (-8.6 kcal/mol, -8.8 kcal/mol, and -10.0 kcal/mol). However, MD simulations revealed that these compounds also stabilized human AIF-M1, identifying Phe482 as a critical off-target anchor.

Species-specific analysis showed variable stability profiles; notably, PkNDH2 exhibited destabilization despite favorable docking scores. This study elucidates the structural basis of the NDH2 selectivity challenge.

It is established that effective pan-Plasmodium inhibition requires simultaneous optimization against human AIF-M1 and careful consideration of variable ortholog dynamics.