Drug Repurposing and High-throughput screening against Phosphomannomutase for the treatment of Cutaneous Leishmaniasis

Abstract

Cutaneous leishmaniasis (CL) is caused by the protozoan parasite L. maxicana is one of the major parasitic diseases throughout the world. Due to the lack of approved vaccines against CL, chemotherapy is the only modern treatment. These treatments have some major consequences including prolonged treatment, parenteral administration, tolerability, teratogenicity, etc. Presently, none of the current CL drugs have high levels of efficacy. Thus, the development of new and safer drugs possessing cost-effective, efficacious, oral and short course drugs is urgently needed. Drug repurposing is another method that can be used for the development of new therapeutic activities.When a new therapeutic activity would have been identified, the entities could be rapidly advanced into clinical trials. Phosphomannomutase (PMM) has become highlighted as potential drug targets due to its important role in the biosynthesis of glycoconjugates.These glycoconjugates are essential for parasite virulence.To identify new promising lead molecules, we have picked 8500 approved drugs for their potential to be repurposed for CL. The library of approved drugs was obtained from Zinc data-base and PMM structure (PDBID: -2i54) was retrieved from protein data bank and used for molecular docking simulation and protein-ligand interaction analysis. The protein structure was validated by the Procheck Ramachandran plot. The virtual screening of the full library of drugs by AutoDock Vina version PyRx 0.8 and selected 46 drug molecules and docking simulations were performed through Glide module of Schrodinger software. Saquinavir and Grazoprevir showed the highest binding affinity -10.144 and -10.131 kcal/mole respectively, was repurposed to be promising drug candidates for CL. To find the stability of complexes (saquinavir-2i54 and grazoprevi-2i54) were performed 100ns molecular dynamics simulation. In the molecular dynamics simulation trajectories of both complexes were analyzed. The results of grazoprevir-2i54 and saquinavir-2i54 complex were showed good stability in the active site of receptor. In conclusion, grazoprevir and saquinavir could be the alternative drugs for the treatment of CL.