Abstract:The complex formed by isopentane, as a model for the isoleucine residue present in the wild-type thymidylate synthase, with 4-mercaptopyridine as a fragment of the thymidylate synthase inhibitor Thymitaq (AG337) is investigated with ab initio quantum chemical calculations at Hartree-Fock and MP2 levels, using the 3-21G* basis set. The binding energy is compared with the binding energies of 4-mercaptopyridine with amino acid residues found in mutant thymidylate synthase enzymes. As compared with isoleucine, ala… Show more
“…All minima of all four different states of protonation of N -formyl- l -histidinamide (Scheme ) were recently determined , by ab initio computations, based on the 3 4 × 4 = 324 minima predicted by multidimensional conformation analysis (MDCA) − In the case of N -formyl- l -histidinamide, 129 out of the 324 structures were identified as minima 3,4 at the RHF/6-31G(d) level of theory. Conformational building units of well-known secondary structural elements, such as the right-handed α-helix (α l ) and that of polyproline II (ε l ), are usually not minima of either N -For- l -Xxx-NH 2 or N -Ac- l -Xxx-NHMe model systems. − However, for N -For- l -His-NH 2 , theoretical calculations provided examples for both types of minima, due to favorable intraresidual interactions. , 1 Four Different Protonation Forms of N -Formyl- l -histidinamide: Indexation of Carbon and Nitrogen Atoms Is Shown on the Top, Location of Torsional Angles Is Shown on the Bottom Molecule Note that N π , N τ , C 2 , C 3 , and C 4 are also referred to as N δ , N ε , C δ , C ε and C γ , respectively. …”
Proton affinity and pK
a values of N-formyl-l-histidinamide are found to vary as a function of its backbone
and/or side-chain orientation. Proton affinities between the cationic and neutral forms of structurally similar
conformers are between −246 and −230 kcal mol-1, while pK
a values associated with the same conformers
are between 6 and 8. For the neutral-to-anion transition, the following ranges were computed −342 > PA >
−350 kcal mol-1 and 18 < pK
a < 22. The protonation state of histidines on the surface of a protein depends
primarily on the pH. Due to protonation or deprotonation, the side-chain and/or backbone orientation of these
histidine residues may undergo considerable changes. Examples are presented and confirmed by ab initio
calculations, where proteins were crystallized under various pH conditions, resulting in the same histidine
residue to adopt different conformations. Furthermore, a hypothesis is given for a protonation-induced
conformational modification of the histidine residue in the catalytic triad of chymotrypsin during catalysis,
which lowers the pK
a value of the catalytic histidine by 1.2 units. Both the experimental and theoretical
results support that proton affinity as well as that pK
a values of histidine residues are strongly conformationally
dependent.
“…All minima of all four different states of protonation of N -formyl- l -histidinamide (Scheme ) were recently determined , by ab initio computations, based on the 3 4 × 4 = 324 minima predicted by multidimensional conformation analysis (MDCA) − In the case of N -formyl- l -histidinamide, 129 out of the 324 structures were identified as minima 3,4 at the RHF/6-31G(d) level of theory. Conformational building units of well-known secondary structural elements, such as the right-handed α-helix (α l ) and that of polyproline II (ε l ), are usually not minima of either N -For- l -Xxx-NH 2 or N -Ac- l -Xxx-NHMe model systems. − However, for N -For- l -His-NH 2 , theoretical calculations provided examples for both types of minima, due to favorable intraresidual interactions. , 1 Four Different Protonation Forms of N -Formyl- l -histidinamide: Indexation of Carbon and Nitrogen Atoms Is Shown on the Top, Location of Torsional Angles Is Shown on the Bottom Molecule Note that N π , N τ , C 2 , C 3 , and C 4 are also referred to as N δ , N ε , C δ , C ε and C γ , respectively. …”
Proton affinity and pK
a values of N-formyl-l-histidinamide are found to vary as a function of its backbone
and/or side-chain orientation. Proton affinities between the cationic and neutral forms of structurally similar
conformers are between −246 and −230 kcal mol-1, while pK
a values associated with the same conformers
are between 6 and 8. For the neutral-to-anion transition, the following ranges were computed −342 > PA >
−350 kcal mol-1 and 18 < pK
a < 22. The protonation state of histidines on the surface of a protein depends
primarily on the pH. Due to protonation or deprotonation, the side-chain and/or backbone orientation of these
histidine residues may undergo considerable changes. Examples are presented and confirmed by ab initio
calculations, where proteins were crystallized under various pH conditions, resulting in the same histidine
residue to adopt different conformations. Furthermore, a hypothesis is given for a protonation-induced
conformational modification of the histidine residue in the catalytic triad of chymotrypsin during catalysis,
which lowers the pK
a value of the catalytic histidine by 1.2 units. Both the experimental and theoretical
results support that proton affinity as well as that pK
a values of histidine residues are strongly conformationally
dependent.
“…These structure-based approaches hold the promise for understanding the structural basis for TS mutations that confer resistance to antifolates, and for designing novel antifolates capable of overcoming these sources of drugresistance [83,84]. The availability of more sophisticated computational tools and greater computer power will expedite these efforts [85].…”
Section: Structure-based Drug Design Of Antifolatesmentioning
Thymidylate synthase (TS) is a well-validated target for cancer chemotherapy. TS was established as the principal target of the widely used anticancer drug 5-fluorouracil (5FU). The 5FU metabolite FdUMP forms a covalent complex with TS that is stabilized by 5-formyl tetrahydrofolate (leucovorin; LV). Numerous chemical strategies have been employed to develop novel TS inhibitors that are superior to 5FU/LV. 5FU is non-ideal as a TS-inhibitory drug because it is only inefficiently converted to FdUMP, while the remainder of the administered dose is converted to toxic metabolites. My laboratory has explored the utility of FdUMP[N] compounds (oligodeoxynucleotides comprised of FdUMP nucleotides) as FdUMP pro-drugs. FdUMP[N] compounds result in potent TS-inhibition, and display many advantages relative to 5FU/LV. A number of other chemical strategies have also been employed to develop pro-drugs, or metabolic precursors of FdUMP, and several of these strategies will be reviewed. In addition to chemical strategies to develop FdUMP pro-drugs, a number of chemical strategies have been devised to develop molecules that resemble the reduced folate co-factor required for TS catalysis. The synthesis of antifolates that have TS-inhibitory activity, such as Raltitrexed, has resulted in compounds that are effective and specific TS-inhibitors and, in some cases, have clinical potential. Chemical strategies that target TS mRNA for destruction are also being explored as potential chemotherapeutics. These diverse chemical approaches to control TS activity in tumor cells for the treatment of cancer will be reviewed.
“…The I108A mutant confers resistance to raltitrexed and thymitaq with respective IC 50 values of 54 and 80 times greater than the wildtype enzyme. These experiments led Sapse et al (2) to perform quantum chemical ab initio calculations on the complexes formed by the binding of thymitaq with various mutants of Ile 108 .…”
Background:The G52S mutation in the Arg 50 loop of thymidylate synthase leads to decreased binding of FdUMP. It has been suggested that the mutation affects the Arg 50 residue (within the Arg 50 loop) responsible for binding the phosphate of FdUMP. The binding of the methylguanidinium moiety as a model for Arg 50 to a methylphosphate entity as a model for FdUMP was investigated with theoretical calculations, as well as the structure of the Arg 50 -Thr 51 -Gly 52 tripeptide in comparison with the Arg 50 -Thr 51 -Ser 52 tripeptide. Methods: Gaussian-98 and PC Spartan programs were used to perform Hartree-Fock and Post-Hartree-Fock
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