De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies

Abstract

Background: Schistosomiasis is the world's second most devastating disease after malaria and the leading cause of disease and mortality for more than 200 million people in developing countries. Cysteine proteases, in particular SmCB1, are the most well-researched biological targets for this disorder.

Objective: To apply computational techniques to design new antischistosomal agents against SmCB1 protein with favorable pharmacokinetic properties.

Methods: The smCB1 receptor-based pharmacophore model was created and used to screen 567,000 fragments from the Enamine library. The best scoring fragments have been linked to build novel compounds that were subjected to molecular docking, MM-GBSA free energy estimation, ADME prediction, and molecular dynamics.

Results: A seven-point pharmacophore hypothesis ADDDRRR was created. The developed hypothesis was used to screen 1.3 M fragment conformations. Among them, 23,732 fragments matched the hypothesis and screened against the protein. The top 50 fragments were used to design new 7745 compounds using the Breed ligand panel which were subjected to docking and MMGBSA binding energy. This led to the identification of 10 compounds with better docking scores (-8.033- -7.483 kcal/mol) and lower-bound free energies (-58.49 - -40.02 kcal/mol) compared to the reference bound ligand. Most of the designed compounds demonstrated good drug-like properties. Concerning Molecular dynamics (MD) simulation results, a low root mean square deviation (RMSD) range (0.25-1.2 Å) was found for the top 3 complexes which indicated their stability.

Conclusion: We identified compounds that could be potential candidates in the search for novel Schistosoma mansoni inhibitors by targeting SmCB1 utilizing various computational tools. Three newly designed compounds namely breed 1, 2, and 3 showed promising affinity to the target as well as favorable drug-like properties which might be considered potential anti-schistosomal agents.

Keywords: docking; molecular dynamics; molecular hybridization; pharmacokinetic properties; pharmacophore modeling.

Figure 1

Study workflow.

Figure 2

SmCB1 protein bound to the reference WRR391 (PDB ID: 5OGQ).

Figure 3

The developed Pharmacophore hypothesis using SmCB1-WRR391 complex (PDB ID: 5OGQ).

Figure 4

Chemical structures of the 10 compounds that showed promising binding affinity against SmCB1 protein.

Figure 5

2D and 3D interaction of (A) Breed 1, (B) Breed 2 and (C) Breed 3 with SmCB1 protein (PDB ID: 5OGQ).

Figure 6

RMSD plot of SmCB1 protein-ligand interaction of top 3 complexes: (A) breed 1 RMSD, (B) breed 2 RMSD, (C) breed 3 RMSD, (D) reference.

Figure 7

Histogram of ligand interaction of top complexes: (A) breed 1, (B) breed 2, (C) breed 3, (D) reference.