Key interactions of pyrimethamine derivatives specific to wild-type and mutant P. falciparum dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations

Abstract

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtPfDHFR), quadruple-mutant (qmPfDHFR), and human (hDHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of des-Cl and m-Cl phenyl analogs of pyrimethamine with various flexible 6-substituents. The interactions of these compounds with DHFR enzymes were investigated by 3 D-QSAR, MD simulations, MM-PBSA, and DFT calculations. CoMFA and CoMSIA models were developed with good predictive abilities for wtPfDHFR and qmPfDHFR. For hDHFR, CoMSIA models combined with clogP descriptor were successfully derived. Binding free energy using MM-PBSA and comparison of per residue decomposition energy analyses with the DFT method at M06-2X/6-31G ++(d,p) level of theory indicated that Asp54 and Phe58 play important roles in the binding of the most potent compound in the series (compound 27) with both wtPfDHFR and qmPfDHFR, whereas Arg59 and Arg122 were additionally found to interact with this inhibitor in qmPfDHFR. For hDHFR, the residues Glu30 and Phe34 but not Arg70, equivalent to Asp54, Phe58, and Arg122 in PfDHFR, also play role in compound 27 binding through strong hydrophobic interactions (Phe34) and hydrogen bond network with Glu30, Ile7, and Val115. From the key interactions identified in the DHFR-inhibitor complexes, a general scheme is proposed for designing new inhibitors selective for PfDHFR that is important for the development of novel antifolate antimalarials.

Communicated by Ramaswamy H. Sarma

Keywords:

• Antimalarials
• DHFR-TS
• 3D-QSAR
• molecular dynamics simulations
• MM-PBSA
• quantum chemical calculations

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by grants from the NSTDA’s Research Chair Grant (P1850116) and Kasetsart University Research and Development Institute, KURDI (FF (KU)11.64). S. Seetin is grateful to the Royal Golden Jubilee PhD Program (RGJ) scholarships (PHD/0236/2558). The Laboratory for Computational and Applied Chemistry (LCAC) at Kasetsart University and National Electronics and Computer Technology Center (NECTEC) are gratefully acknowledged for computational and Sybyl software resources. The National Center for Genetic Engineering and Biotechnology (BIOTEC), Research Network NANOTEC-Kasetsart on NanoCatalysts and NanoMaterials for Sustainable Energy and Environment (RNN-CMSEE) and Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, Kasetsart University are gratefully acknowledged for partial research support. Thanks are also due to Dr. Philip James Shaw, BIOTEC, NSTDA for helpful reading of the manuscript.