In silico screening of chalcone derivatives as potential inhibitors of dihydrofolate reductase: Assessment using molecular docking, paired potential and molecular hydrophobic potential studies

Abstract

Objectives

Enzyme dihydro foliate reductase (DHFR) is involved in synthesis of DNA and consequently, has long been recognized to have utmost therapeutic significance, since its inactivation can be targeted in numerous infectious as well as noninfectious diseases. In the present studies molecular docking of chalcone derivatives with human as well as Mycobacterial DHFR, followed by paired potential and hydrophobic potential analysis were carried out to understand the novel chalcone–DHFR interactions.

Methods

Molecular docking was carried out using GOLD and AutoDock software, paired potential analysis was performed employing on-line program DSX-ONLINE and molecular hydrophobic potential (MHP) analysis was done using web-based program PLATINUM.

Results

Results obtained from docking study, drug score potential and MHP analysis coincide with experimental findings. Molecular property analysis indicates that given compounds follows Lipinski's rule of five. Compound number 1 exhibited best binding energy (−8.02 kcal/mol) in human DHFR while compound number 6 (−7.36 kcal/mol), 9 (−7.32 kcal/mol), 10 (−7.31 kcal/mol) and 11 (−8.25 kcal/mol) demonstrated favorable binding score in Mycobacterial DHFR.

Conclusions

Per atom score contribution of chalcone derivatives obtained by paired potential analysis indicate participation of conserved as well as few new residues are expected to be involved in inhibition of DHFR. MHP analysis of chalcone–DHFR complexes revealed important role of hydrophobic contact in inhibition; additionally, individual chemical scaffold on chalcone derivatives that contribute in lipophilicity has been identified. This data is expected to be further explored for the design and development of novel class of DHFR inhibitors using chalcone scaffold.