Molecular insights into anti-Protozoal action of natural compounds against : a molecular simulation study.

The current study used the major target protein lactate dehydrogenase to identify potential binders. Our approach was a comprehensive three-step screening of 2,569 natural compounds. First, we used molecular docking techniques, followed by an advanced DeepPurpose ML model for virtual screening. The final step involved meticulous re-docking and detailed interaction analysis. The known inhibitor FX11 was considered as a control that was used for comparative analysis. Our screening process led to the identification of three promising compounds: 5353794, 18475114, and 25229652. These compounds were chosen due to their exceptional ability to form hydrogen bonds and their high binding scores with the protein. Here, all three hits showed H-bonds with the functional residues (Asn122 and Thr231) of protein, while 25229652 also showed H-bond with the catalytic site residue (His177). RMSD behaviour reflected stable and consistent complex formation for all the compounds in their last 30 ns trajectories. Principal component analysis (PCA) and free energy landscape (FEL) showed a high frequency of favourable low free energy states. Using the MM/GBSA calculation, compounds 5353794 (ΔG = -34.92 kcal/mol) and 18475114 (ΔG = -34.66 kcal/mol) had the highest binding affinity with the protein however, 25229652 (ΔG = -22.62 kcal/mol) had ΔG comparable to the control FX11. These natural compounds not only show the potential for hindering lactate dehydrogenase but also open new avenues in its drug development. Their strong binding properties and stable interactions mark them as the prime candidates for further research and experimental validation as anti-cryptosporidiosis agents.Communicated by Ramaswamy H. Sarma.