Modelling and Informatics in the Analysis of P. falciparum DHFR Enzyme Inhibitors

Abstract

Malaria is one of the most prevalent diseases of our planet which claims millions of lives annually. Plasmodium falciparum is the causative agent of majority of the mortality and morbidity associated with malaria particularly in tropical countries. Resistance of the parasite to the currently available chemotherapeutic agents poses a serious threat to human being. Inhibition of P. falciparum dihydrofolate reductase (DHFR) enzyme has been used as one of the strategies in curbing malaria. However, due to mutation in the active-site of the enzyme particularly at 16, 51, 59, 108, and 164 residues, the parasite developed resistance to most of antifolate drugs such as cycloguanil and pyrimethamine. Thus, design of new and potent antimalarial agents which are effective against both wild-type and mutant enzymes is very essential in order to minimize burden of P. falciparum malaria. Computer-aided drug design approaches are playing a crucial role in the design of potential antimalarial drug candidates. In this article, molecular modelling studies based on docking, pharmacophore mapping, QSAR, homology modelling, and quantum chemical studies are reviewed. The importance of these methods in understanding mechanism of drug resistance at a molecular level, and design of antimalarial drug candidates are discussed briefly. The examples mentioned in the review could give insights into the wide range of possibilities of using computer-aided drug design (CADD) methodologies.

Crystal Structure of Bacillus anthracis Dihydrofolate Reductase with the Dihydrophthalazine-Based Trimethoprim Derivative RAB1 Provides a Structural Explanation of Potency and Selectivity

“…One proposal is that selectivity arises from the volume of the binding site (16,49). This is directly related to TMP resistance and generally correlates with more favorable K m values for FAH 2 (3,12,39,45), thus making it harder to displace. However, exceptions that are TMP sensitive with a low K m for FAH 2 do exist, such as Lactobacillus casei (24).…”

“…DHFR is found in both prokaryotes and eukaryotes, and all DHFR enzymes studied to date are targeted by the chemotherapeutic methotrexate (MTX) (40). Selectivity can be achieved, such as targeting plasmodial organisms with pyrimethamine (2). In addition, some prokaryotic DHFR's are selectively inhibited by trimethoprim (TMP) (13,28,51).…”

New approaches to the development of anti-protozoan drug candidates: a review of patents

“…Furthermore, using these methodologies it is feasible to investigate the structural factors responsible for selectivity of some target enzymes with their inhibitors, and therefore hasten much needed research. [118][119][120][121] However, it should be kept in mind that computers are an essential tool in modern medicinal chemistry. Currently, computational approaches and 3D visualization are not used simply to depict pretty pictures of molecules in biological systems; these powerful computational tools allow one to obtain insights on the interaction between enzyme-substrate, mechanism reaction, statistical behavior of molecules and much more, at the molecular level, contributing significantly to the problem solving in biological systems.…”

Structure−Activity Relationship and Comparative Docking Studies for Cycloguanil Analogs as PfDHFR-TS Inhibitors

“…A double mutation, A16V+S108T, is specific for resistance to the marketed drug cycloguanil. Over the past few years, several computational techniques have been applied to better understand Pf DHFR-TS-ligand interactions 10. Currently there are four crystal structures of protozoal DHFR available in the Protein Data Bank, including the wild type Pf DHFR-TS complexed with triazine inhibitor WR99210 (1j3i),11 a double mutant Pf DHFR-TS complexed with pyrimethamine (1j3j),11 a quadruple mutant Pf DHFR-TS complexed with WR99210 (1j3k)11 and wild type Plasmodium vivax DHFR-TS complexed with pyrimethamine (2bl9) 12.…”