Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme

Abstract

Design and discovery of new potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), equally active against both the wild-type and mutant strains, is urgently needed. In this study, a computer-aided molecular design approach that involved ab initio molecular orbital and density functional theory calculations, along with molecular electrostatic potential analysis, and molecular docking studies was employed to design 15 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme. Visual inspection of the binding modes of the compounds demonstrated that they all interact, via H-bond interactions, with key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14) similar to those of WR99210 (3) in the active site of the enzymes used in the study. These interactions are known to be essential for enzyme inhibition. These compounds showed better or comparable binding affinities to that of the bound ligand (WR99210). In silico toxicity predictions, carried out using TOPKAT software, also indicated that the compounds are non-toxic.

Spectroscopic investigation (FT-IR and FT-Raman), vibrational assignments, HOMO–LUMO, NBO, MEP analysis and molecular docking study of 2-(4-hydroxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide

“…The (Fig. 7) containing the amino acid residues present at the active sites [74]. This conferred its high affinity for the enzyme.…”

VSDK: Virtual screening of small molecules using AutoDock Vina on Windows platform

“…On the other hand, docking application tools, in which the ligand-macromolecule interaction conformation is predicted and scored in terms of binding free energy between the ligand and macromolecule, have made a remarkable progress in their accuracy and speed, although molecular docking is an extremely demanding task for computer resources. There is no question about the fact that the CAMD (computer-aided molecular design) approach is becoming a common practice in drug discovery and development [1]. Owing to all these advancements in structure data bases and application software, a highthrough- put virtual screening technology, in which one can screen thousands of compounds for their binding affinity against a target macromolecule, has been developed and utilized to aid in the drug discovery.…”

Origins of the specificity of inhibitor P218 toward wild-type and mutantPfDHFR: a molecular dynamics analysis

“…Further, by using molecular docking approach, 2,4-diaminoquinazoline and 2,4-diaminopteridine analogs were reported as potential inhibitors of PfDHFR . Multiple computational approaches like ab initio molecular orbital and density functional theory calculations, along with the molecular electrostatic potential analysis, and molecular docking were also utilized by our research group for the design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme (Adane & Bharatam, 2011). Many scientific groups have also identified many novel classes of PfDHFR inhibitors such as 2,4-diaminopyrimidines (Falco, Goodwin, Hitchings, Rollo, & Russell, 1951), 2-amino-1,4-dihydro-4,4,7,8-tetramethyl-s-triazino(1,2-a)benzimida zole and Trp-P-2 series (Toyoda et al, 1997), 5-Benzyl-2,4-diamonopyrimidines (Sirichaiwat et al, 2004), novel biguanide analogs (RJF001302, RJF00670 and RJF00719) (Dasgupta et al, 2009), 2-methyl-6-ureido-4-quinolinamides (Madapa et al, 2009, 4-anilinoquinoline triazines , 1,2,3-Triazole tethered β-lactam and 7-chloroquinoline bifunctional hybrids , hybrid phenylthiazolyl-1,3,5-triazine derivatives (Gahtori et al, 2012), 4-aminoquinoline and 1,3,5-triazine derivatives Bhat et al, 2013), and 2-Aminopyrimidinebased 4-aminoquinoline antiplasmodial agents (Singh, Kaur et al, 2012).…”