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Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase

1
Department of Biochemistry and Molecular Biology, Howard University College of Medicine, 520 “W” Street NW, Washington, D. C. 20059, USA
2
Department of Pharmacology, Howard University College of Medicine, 520 “W” Street NW, Washington, D. C. 20059, USA
3
Department of Medicine, Howard University College of Medicine, 2014 Georgia Ave. NW, Washington, D. C. 20059, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2002, 3(11), 1188-1202; https://0-doi-org.brum.beds.ac.uk/10.3390/i3111188
Received: 7 June 2002 / Accepted: 30 October 2002 / Published: 30 November 2002
The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR):trimethoprim:NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes: P. carinii DHFR:piritrexim:NADPH, P. carinii DHFR:epiroprim:NADPH, and P. carinii DHFR:trimetrexate:NADPH. Each of these complexes, including the original trimethoprim complex was then modeled in 60 angstrom cubes of explicit water and minimized to a rms gradient between 1.0 to 3.0 x 10-5 kcal/angstrom. Subsequently, each antifolate structure was subdivided into distinct substructural regions. The minimized complexes were used to calculate interaction energies for each intact antifolate and its corresponding substructural regions with the P. carinii DHFR binding site residues, the DHFR protein, the solvated complex ( which consists of P. carinii DHFR, NADPH, and solvent water), solvent water alone, and NADPH. Antifolate substructural regions which contained nitrogen and carbon atoms in an aromatic environment (i. e. the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions) contributed most to the stability of antifolate interactions, while interaction energies for the hydrocarbon aromatic rings, methoxy, and ethoxy groups were much less stable. Additionally, interaction energy analyses were calculated for carbon and nitrogen atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions and for the carbon and oxygen atoms of methoxy and ethoxy subregions. The contributions of hydrogen atoms were included with those of the carbon, nitrogen and oxygen atoms to which they are attached. These analyses revealed that the carbon atoms of the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions generally contributed most to the stability of those regions. Carbon atoms also contributed favorably to the stability of the methoxy group interactions. Those substructural regions which exhibit relatively unfavorable interaction energies may constitute important modification targets in the design of improved P. carinii DHFR inhibitors. Interaction energies for different groups of atoms within the substructural regions suggest strategies for modification of the substructural regions. View Full-Text
Keywords: antifolates; interaction energy; DHFR binding antifolates; interaction energy; DHFR binding
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MDPI and ACS Style

Pitts, C.; Yin, J.; Bowen, D.; Maxwell, C.J.; Southerland, W.M. Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase. Int. J. Mol. Sci. 2002, 3, 1188-1202. https://0-doi-org.brum.beds.ac.uk/10.3390/i3111188

AMA Style

Pitts C, Yin J, Bowen D, Maxwell CJ, Southerland WM. Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase. International Journal of Molecular Sciences. 2002; 3(11):1188-1202. https://0-doi-org.brum.beds.ac.uk/10.3390/i3111188

Chicago/Turabian Style

Pitts, Conrad, Jian Yin, Donnell Bowen, Celia J. Maxwell, and William M. Southerland 2002. "Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase" International Journal of Molecular Sciences 3, no. 11: 1188-1202. https://0-doi-org.brum.beds.ac.uk/10.3390/i3111188

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