Abstract
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).
Highlights
Plasmodium falciparum dihydrofolate reductase is a key enzyme responsible for the Plasmodium parasite’s reproductive cycle
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 or non-desirable responses on the body or both [6,7,8]
The geometry of Cyc derivatives are optimized by Gaussian
Summary
Plasmodium falciparum dihydrofolate reductase (pf DHFR) is a key enzyme responsible for the Plasmodium parasite’s reproductive cycle. Double mutations at residue 16 (alanine mutates to valine) and at residue 108 (serine mutates to threonine) confer cycloguanil (Cyc) resistance in the double mutant variant pf DHFR (A16V + S108T) [1,2]. To tackle this problem, Cyc derivatives are designed and experimentally tested against both wild-type and mutant pf DHFR (A16V + S108T). The effects of changing the substituent at C-2 and the shifting of p-chlorophenyl to the m-position at N-1, results in the lowering of the inhibition constant (Ki ) between the Cyc derivative and mutant pf DHFR at the nanomolar level [5].
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