Binding investigation of pyrimethamine derivatives complexes with wild-type and mutant P. falciparum dihydrofolate reductase using MD simulations and quantum chemical calculations Sasipha seetin a,b, Patchreenart Saparpakorn a,b, Jarunee Vanichtanankulc, Sumalee Kamchonwongpaisan c, and Supa Hannongbua a,b*
a Department of Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
b Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
c National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Klong Luang, PathumThani 12120, Thailand
*Corresponding authors: Supa Hannongbua, email: fscisph[at]ku.ac.th
Abstract
Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfDHFR-TS) is an important target enzyme and is regarded as an interesting target for designing antimalarial drugs. However, drug resistance is the main reason for unsuccessful malaria treatment. A series of des-Cl and m-Cl phenyl analogues of pyrimethamine with various flexible 6-substituents were investivated, based on MD simulations, quantum chemical calculations, and MM-PBSA, to comprehend of how the potential inhibitor, compound27, interact with wild-type (wtPfDHFR), quadruple-mutant (qmPfDHFR), and human (hDHFR) enzymes. Compound27 complexed with the three DHFR enzymes were obtained to reach the stability by using MD simulations, followed by confirming the binding interaction of key residues which were analyzed by quantum chemical calculations and MM-PBSA simulation. It was found that Asp54 and Phe58 play important roles in wtPfDHFR and qmPfDHFR, while Arg59 and Arg122 found interactions with compound 27 in qmPfDHFR system. On the other hand, the position of Arg122 in wtPfDHFR and qmPfDHFR is found to be equivalent to Arg70 which is unlikely to bind in hDHFR. For the hDHFR, strong hydrophobic interactions with Phe34 and hydrogen bonding with Ile7, Val8, and Glu30 were found. According to key interaction findings of compound27, it can provide valuable suggestions for further novel antimalarials development.
Keywords: Antimalarials, DHFR-TS, Molecular dynamics simulations, MM-PBSA, Quantum chemical calculations
