Identification of Selective Inhibitors of Ld DHFR Enzyme Using Pharmacoinformatic Methods
Vishnu Kumar Sharma, Prasad V. Bharatam · Journal of Computational Biology · 2020
Dihydrofolate reductase (DHFR) is a well-known enzyme of the folate metabolic pathway and it is a validated drug target for leishmaniasis. However, only a few leads are reported against Leishmania donovani DHFR ( Ld DHFR), and thus, there is a need to identify new inhibitors. In this article, pharmacoinformatic tools such as molecular docking, virtual screening, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, and molecular dynamics (MD) simulations were utilized to identify potential Ld DHFR inhibitors. Initially, a natural DHFR substrate (dihydrofolate), a classical DHFR inhibitor (methotrexate), and a potent Ld DHFR inhibitor, that is, “5-(3-(octyloxy)benzyl)pyrimidine-2,4-diamine” (LEAD) were docked in the active site of the Ld DHFR and MD simulated to understand the binding mode characteristics of the substrates/inhibitors in the Ld DHFR. The shape of the LEAD molecule was used as a query for shape-based virtual screening, while the three-dimensional structure of Ld DHFR was utilized for docking-based virtual screening. In silico ADMET factors were also considered during virtual screening. These two screening processes yielded 25 suitable hits, which were further validated for their selectivity toward Ld DHFR using molecular docking and prime molecular mechanics/generalized born surface area analysis in the human DHFR ( Hs DHFR). Best six hits, which were selective and energetically favorable for the Ld DHFR, were chosen for MD simulations. The MD analysis showed that four of the hits exhibited very good binding affinity for Ld DHFR with respect to Hs DHFR, and two hits were found to be more selective than the reported potent Ld DHFR inhibitor. The present study thus identifies hits that can be further designed and modified as potent Ld DHFR inhibitors.