No abstract

Due to the lack of approved vaccines against Cutaneous leishmaniasis (CL), chemotherapy is the only treatment option. Presently, none of the current CL drugs have high levels of efficacy and safety profiles. Thus, the development of new and safer drugs is urgently needed. Drug repurposing can be used for the development of new therapeutic activities. Phosphomannomutase (PMM) has become highlighted as a potential drug target due to its important role in the biosynthesis of glycoconjugates which is essential for parasite virulence. To identify new promising lead molecules, we have performed virtual screening of 8,500 drugs and selected 46 drugs for docking simulation through the Glide module of Schrodinger software. The saquinavir and grazoprevir showed the highest binding affinity (-10.144 and -10.131 kcal/mole). To find the stability of both complexes, molecular dynamics (MD) simulations were performed at 100ns. The grazoprevir-2i54 and saquinavir-2i54 complexes showed good stability in the active site of the receptor. It could be an alternative drug for the treatment of CL.

Visceral leishmaniasis (VL) is caused by Leishmania donovani (Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target against L. donovani in the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high‐throughput virtual screening of 8630 ZINC database ligands against Leishmania donovani ornithine decarboxylase (Ld ODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, −10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine). In‐silico findings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.

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.