Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase

Abstract

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,

In Vivo Imaging of Bioluminescent Escherichia coli in a Cutaneous Wound Infection Model for Evaluation of an Antibiotic Therapy

“…The D-luciferin substrate for P. pyralis luciferase and TMP-SMX are amphipathic molecules (i.e., hydrophilic and hydrophobic areas are present within the same molecule) (19,32). The D-luciferin substrate and SMX-TMP antibiotic must permeate the outer membrane on the way into the periplasmic space and the cell, which means that that the outer membrane has special sieving properties.…”

The electronic density obtained from a QTAIM analysis used as molecular descriptor. A study performed in a new series of DHFR inhibitors

“…In the first step, seven new compounds were synthesized and then they were evaluated for their inhibitory activities against human DHFR. These results were added to thirteen compounds reported by Gangjee et al (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) [16], two compounds reported in our earlier work (14a and 15a) [5] and two new compounds (14e and 15f) recently reported in reference [17] in order to have a more complete and representative number of compounds (25 molecules in the complete series ( Figure 1 and Table 1)). In the next step, we performed MD simulations, QM calculations (using different levels of theory) and QTAIM analysis with the aim to obtain a correlation which allows the discrimination between compounds possessing similar affinities by the enzyme.…”

“…Dihydrofolate reductase (DHFR) is an excellent molecular target for this study because it has been and is currently studied by using different molecular modeling techniques [6][7][8][9]. Kerrigan et al have reported an interesting review about recent progress in molecular dynamics simulations of DHFR [10] and they conclude that "molecular mechanics calculations can work well to model the initial binding step of an inhibitor or substrate with…”