Theoretical Investigation of the Enantioselective Complexations between pfDHFR and Cycloguanil Derivatives

Point mutations in Plasmodium falciparum dihydrofolate reductase (pfDHFR), especially the double mutant variant (A16V + S108T), led to ineffective inhibiting by cycloguanil (Cyc). Cycloguanil derivatives showed good inhibiting properties against wild-type and mutant pfDHFR with an inhibition constant as low as the nanomolar level. However, there have been no reports on the stereochemistry of the compounds, and this is important because the pure enantiomeric form of a chiral drug can exert desirable, as well as non-desirable responses on the body or both. In this work, three-dimensional structures of Cyc derivatives in R and S configuration were constructed and optimized using Hartree-Fock/6-31G (d,p). Their structures were docked into the binding pocket of wild-type and double mutant (A16V + S108T) pfDHFR, complexed with nicotinamide adenine dinucleotide phosphate (NADPH). Results indicate that both wild-type and mutant pfDHFR are enantioselective towards enantiomeric Cyc derivatives (R and S configuration).