Molecular docking and simulation analysis of selected herbal compounds against GP63, FPPS, and NMT, three important Leishmania major proteins.

Background and purpose: Leishmaniasis has been categorized as one of the most significant tropical illnesses, often ignored. This study aimed to find effective plant compounds to combat the pathogenicity of the Leishmania parasite.

Experimental approach: The 3D structures of the zinc leishmanolysin glycoprotein 63 (GP63), farnesyl diphosphate synthase (FPPS), and N-myristoyltransferase (NMT) proteins from L. major, as well as blockers and 4000 herbal compounds, were retrieved from the PubChem database. A molecular docking study was performed on Leishmania proteins using PyRx software. The activity, ADMET characteristics, and daily carcinogenicity were taken from "Swiss ADME", "way 2 drug", and "Lazar" websites. Molecules with the greatest docking scores for each protein were chosen for molecular dynamics simulation using GROMACS.

Findings/results: Molecular docking experiments revealed that withaperuvin D and lagerstannin A have a strong affinity for the GP63 protein. Moreover, strictinin showed the highest binding affinity for FPPS, whereas the top compounds for NMT were chelidimerine, friedelin, and hypericin. Additionally, luteolin 3'-o-glucuronide, protohypericin, and amentoflavone had high binding affinity for all three proteins, and amentoflavone had the highest binding energy of all the proteins. Based on RMSD, RMSF, Rg, PCA, MM/PBSA binding energy, and SASA, the molecular dynamic simulation results indicated relatively stable interactions between these ligands and the mentioned proteins during the simulation period.

Conclusion and implications: Given the pharmaceutical information, the mentioned substances may have anti-inflammatory and wound-healing properties in addition to blocking proteins. Therefore, experimentally examining these compounds in the future can help control and treat leishmaniasis.