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- Ersmark, Karolina, et al.
(författare)
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C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II : synthesis and theoretical predictions
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:17, s. 3723-3733
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Tidskriftsartikel (refereegranskat)abstract
- A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results.
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| 5. |
- Feierberg, Isabella, et al.
(författare)
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Computational modeling of enzymatic keto-enol isomerization reactions
- 2002
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 108:2, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- Catalysis of proton abstraction from nonacidic carbon atoms adjacent to a carbonyl or carboxylate group is a fundamental reaction in enzymology that has been extensively studied during the last few decades. Enzymes catalyzing these reactions, which normally involve labile enolic intermediates, need to overcome large pK a differences between the reacting groups as well as high intrinsic free-energy barriers. Here, we present an overview of results from recent computer simulation studies of keto-enol isomerization reactions catalyzed by the enzymes glyoxalase I, triosephopsphate isomerase and ketosteroid isomerase. For all three enzymes it is found that electrostatic stabilization of the transient enolate intermediates, either by charge–charge interactions or by hydrogen bonding, accounts for the main part of the activation free-energy barrier reduction. Another catalytic effect observed in all cases is the reduction of the reorganization energy by the enzyme active site. Some other factors that have been proposed to be important for these reactions are also discussed and evaluated.
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| 6. |
- Feierberg, Isabella, et al.
(författare)
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Computer simulation of primary kinetic isotope effects in the proposed rate-limiting step of the glyoxalase I catalyzed reaction
- 2000
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 275:30, s. 22657-22662
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Tidskriftsartikel (refereegranskat)abstract
- The proposed rate-limiting step of the glyoxalase I catalyzed reaction is the proton abstraction from the C1 carbon of the substrate by Glu172. Here we examine primary kinetic isotope effects and the influence of quantum dynamics on this process by computer simulations. The calculations utilize the empirical valence bond method in combination with the molecular dynamics free energy perturbation technique and path integral simulations. For the enzyme-catalyzed reaction a H/D kinetic isotope effect of 5.0 ± 1.3 is predicted in reasonable agreement with the experimental result of about 3. Furthermore, the magnitude of quantum mechanical effects is found to be very similar for the enzyme reaction and the corresponding uncatalyzed process in solution, in agreement with other studies. The problems associated with attaining the required accuracy in order for the present approach to be useful as a diagnostic tool for the study of enzyme reactions are also discussed.
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| 7. |
- Feierberg, Isabella, et al.
(författare)
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The catalytic power of ketosteroid isomerase investigated by computer simulation
- 2002
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 41:52, s. 15728-15735
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Tidskriftsartikel (refereegranskat)abstract
- Ketosteroid isomerase (KSI) catalyzes the isomerization of Delta(5)-3-ketosteroids and Delta(4)-3-ketosteroids at very high rates. Here we examine the principles underlying the catalytic efficiency of KSI by computer simulations using the empirical valence bond method in combination with molecular dynamics free energy perturbation simulations. The simulations reproduce available kinetic and structural data very well and allow us to examine several features of the catalytic mechanism in detail. It is found that about 60% of the rate enhancement is due to stabilization of the negatively charged dienolate intermediate by hydrogen bonding. The critical H-bond between Tyr16 and the intermediate is found to be a normal ionic H-bond with the preferred proton location on the tyrosine residue. The remaining 40% of the catalytic effect originates from a reduction of the reorganization energy of the reaction. The possibility of an active site water molecule occupying the empty cavity adjacent to the catalytic base (Asp40) is also addressed. The existence of such a water molecule could explain how the enzyme manages to maintain a low pK(a) for the general base residue.
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| 8. |
- Graffner-Nordberg, Malin, et al.
(författare)
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Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii
- 2004
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 22:1, s. 43-54
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Tidskriftsartikel (refereegranskat)abstract
- A series of dihydrofolate reductase (DHFR) inhibitors, where the methylenamino-bridge of non-classical inhibitors was replaced with an ester function, have been prepared as potential soft drugs intended for inhalation against Pneumocystis carinii pneumonia (PCP). Several of the new ester-based inhibitors that should serve as good substrates for the ubiquitous esterases and possibly constitute safer alternatives to metabolically stable DHFR inhibitors administered orally, were found to be potent inhibitors of P. carinii DHFR (pcDHFR). Although the objectives of the present program is to achieve a favorable toxicity profile by applying the soft drug concept, a high preference for inhibition of the fungal DHFR versus the mammalian DHFR is still desirable to suppress host toxicity at the site of administration. Compounds with a slight preference for the fungal enzyme were identified. The selection of the target compounds for synthesis was partly guided by an automated docking and scoring procedure as well as molecular dynamics simulations. The modest selectivity of the synthesized inhibitors was reasonably well predicted, although a correct ranking of the relative affinities was not successful in all cases.
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