Shape- and Chemical Feature-Based 3D-Pharmacophore Model Generation and Virtual Screening: Identification of Potential Leads forP. falciparumDHFR Enzyme Inhibition

Abstract

Plasmodium falciparum dihydrofolate reductase (Pf DHFR) enzyme is one of the validated targets in the treatment of malaria using typical antifolates such as cycloguanil and pyrimethamine. However, point mutations at amino acid residues such as Ala16, Ile51, Cys59, Ser108 and Ile164 in the active site of the wild‐type enzyme resulted in a widespread resistance of the parasite to these drugs. Thus, design and discovery of new potential Pf DHFR inhibitors, equally active against both the wild‐type and mutant strains, is an urgent need. Catalyst software was used to generate a 3D pharmacophore query based on the bioactive conformation of WR99210 extracted from the X‐ray crystal structure of quadruple mutant PfDHFR enzyme. Validation criteria based on the experimentally determined conformation of WR99210 and its key interactions with the protein were considered to identify hits from two chemical databases, namely, NCI2000 and Maybridge2004 using different virtual filters. Virtual screening based on FlexX, GOLD and Glide docking programs resulted in a total of 73 hits. The hits reported in this article showed good potential to be inhibitors of the above Pf DHFRs based on their (i) best‐fit values (ii) binding scores (iii) binding modes and (iv) interactions with the key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14).