Computer-aided discovery of bis-indole derivatives as multi-target drugs against cancer and bacterial infections: DFT, docking, virtual screening, and molecular dynamics studies

Abstract

Recently, more complex diseases of seemingly incurable pathology have demonstrated the need for potent and multi-target drugs. Specific to many cancers and bacterial diseases, more than 100 bis-indole compounds along with a commercialized drug, olaparib are screened against fifteen protein targets (eleven cancer and four bacterial), which have direct roles in tumorigenesis, cancer progression, or pathogenesis. Successive refinements are performed employing the density functional theory (DFT), pharmacokinetics, and virtual screening. Eight potential drugs, of which three as multi-target agents against both bacteria and cancer, are shortlisted. Molecular dynamics simulation was employed to check the stability of the discovered drugs in their docked configurations along with principal component analysis and molecular mechanics Poisson-Boltzmann surface area-based binding free energy calculation. All of these complexes have lower binding free energies. During dynamics, after some initial run, the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) of every shortlisted target-drug complex quickly reach a plateau, indicating the stability of the docked complex and potential inhibitory property of the shortlisted drugs. A proposed drug can unprecedentedly inhibit six targets. Due to the presence of prevailing bis-indole-scaffold as evident in many well-known drugs, the shortlisted compounds can be envisaged to emerge as very effective drugs for cancers and bacterial infections, which encourages experimental studies to validate them.