Identification of Potential Multitarget Antimalarial Drugs
- Ekachai Jenwitheesuk, DVM, PhD;
- Ram Samudrala, PhD
To the Editor: Malaria is one of the deadliest tropical diseases, causing more than 300 million infections yearly.1 Successful clearance of the malarial parasites, Plasmodium species, from a patient’s body by antimalarial drugs is impeded by the emergence of drug-resistant strains. Drugs that effectively eliminate Plasmodium with short treatment duration reduce risk of treatment failure and emergence of drug-resistant strains.1
Antimalarial drugs currently target single Plasmodium proteins. Effective therapeutic regimens require a combination of drugs that have different mechanisms of action during the same stage of the parasite’s life cycle.1 However, malaria is a disease that occurs mostly in tropical and subtropical areas, where patients have limited access to drugs, and combination drug regimens may not succeed due to poor adherence.2 Multitarget drugs are currently being used extensively to treat both infectious and inherited diseases.3 New antimalarial therapies that include multitarget drugs may have higher efficacy than single-target drugs and provide a simpler regimen for antimalarial therapy.4 Our purpose in this study was to predict a list of drugs that will bind to the active site of multiple Plasmodium falciparum proteins with high affinity.
Methods
We used a computational protein-inhibitor docking with dynamics protocol5 to calculate the binding affinities of 1105 approved and 1239 experimental drugs (obtained from ChemBank6) against 13 Plasmodium proteins whose structures have been determined by x-ray crystallography. Binding affinity calculations were carried out using AutoDock version 3.0.5 with a Lamarckian genetic algorithm (The Scripps Research Institute, La Jolla, Calif). We first placed each drug into the active site of the protein to find the most stable binding mode. The protein-drug complexes were consequently solvated in a water shell with sodium and chloride ions. We applied 100 steps of energy minimization followed by 0.1 ps of molecular dynamics simulation to each complex using XPLOR version 3.851 (Yale University, New Haven, Conn). The conformations at 0.1 ps were used for the protein-drug binding affinity calculations.
For each protein, a given drug was docked into the active site and allowed to move in an exhaustive manner to find the most stable binding conformation. The protein-drug binding affinity in terms of the inhibitory constant (Ki) was calculated every time the drug molecule was moved. After repeating this procedure for all of the drugs for each protein, the 20 drugs with the lowest Ki values were considered high-affinity drug candidates. Further details of the molecular dynamics simulation and docking protocols are available elsewhere.5
Results
We predicted 20 multitarget drugs that showed high affinity across 2 or more proteins (Figure). Four are drugs approved by the US Food and Drug Administration for treatment of diseases other than malaria: KN62 (targeting 3 proteins), protoporphyrin IX, phthalylsulfathiazole, and sulfaphenazole (targeting 2 proteins each). The other 16 are experimental, each targeting up to 6 proteins. The best drugs in terms of multitarget functionality were STI-571 (targeting 6 proteins), bisindolylmaleimide x, GW8510, and Piper (targeting 5 proteins each). The best combination of 2 drugs was bisindolylmaleimide x and GW8510, which together target 10 Plasmodium proteins. An analysis of 3 known single-target antimalarial drugs against these proteins showed that our calculated Kis for these drugs compared well with experimentally determined values (when available) and that the inhibitory activity usually ranked within the top 5th percentile compared with our entire set of drugs (Table).
Figure. Binding Patterns of 4 Approved (Blue) and 16 Experimental (Black) Multitarget Drugs to 13 Plasmodium falciparum Proteins
These drugs target the active site of 2-6 proteins with high affinity.
Table. Comparison of the Inhibitory Activities of 3 Antimalarial Drugs and the Drugs Predicted to Have the Highest Binding Affinity*
Conclusions
Promising vaccines targeting multiple Plasmodium proteins have been evaluated.9-10 In a similar fashion, we propose designing new antimalarial drugs that simultaneously target multiple Plasmodium proteins. Our computational drug screening protocol provides evidence for 20 approved or experimental drugs that bind strongly to 13 Plasmodium proteins. We recommend that these drug candidates be experimentally tested for inhibition of Plasmodium growth and used as a starting point for further design of a high-efficacy multitarget antimalarial drug.
Author Contributions: Dr Jenwitheesuk had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design; analysis and interpretation of data: Jenwitheesuk, Samudrala.
Drafting of the manuscript: Jenwitheesuk.
Critical revision of the manuscript for important intellectual content; obtained funding; study supervision: Samudrala.
Financial Disclosures: None reported.
Funding/Support: This work was supported in part by a NSF CAREER award, NSF grant DBI 0217241, NIH grant GM068152, a Searle Scholar Award, and the Puget Sound Partners in Global Health.
Role of the Sponsor: The grant sponsors had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
