Phosphonates as inhibitors for Pks13-TE
Hypothesis for the aim 1 of the proposed project is that the fluorinated α–Aminophosphonates as a covalent irreversible inhibitor for the Mtb Pks13-TE by scission of the P-C bond. Previous studies have shown the fluorinated aminophosphonates (FAPs) demonstrated serine esterases inhibition via scission of the P-C bond as shown in Figure 2.1.A 4. FAPs are known to irreversibly inhibit serine esterases such as acetylcholinesterase16 , neuropathy target esterase, carboxylesterases 17 , etc. Since Pks13-TE contains serine as the nucleophile in the catalytic site, FAPs can be tested against Pks13-TE. Aim 2: Characterize the inhibitory activity of thiophene compounds against Pks13-TE using Isothermal Titration Calorimetry
Zhang, W et al. has Recently shown that thiophene compounds are expected to form non-covalent interactions with Pks13-TE 18. The 4MH-based assay, which is explained in aim 1 will be used to assess the thiophenes inhibitory activity of each thiophene compound that are received from Dr. Steve Sucheck’s …show more content…
Also, the reaction stoichiometry can obtain by the molar ratio at the center of the binding of the isotherm. The heat release per mole of ligand bound, ∆H can be derived directly from the isotherm which reflects the strength of the interactions between pks13-TE and thiophene compounds23-24 . The magnitude of the change in entropy(ΔS) reflects the entropic contributions to the binding 24. The change in heat capacity (ΔCp) suggests the structural information of the Pks13-TE and thiophene complex. The negative ΔCp value indicates an increase in hydrophobic interactions of the complex upon binding. Therefore, using a single ITC experiment can afford the information on binding interactions, nature of the interactions and also the thermodynamic information without using any labels
Hypothesis for the aim 1 of the proposed project is that the fluorinated α–Aminophosphonates as a covalent irreversible inhibitor for the Mtb Pks13-TE by scission of the P-C bond. Previous studies have shown the fluorinated aminophosphonates (FAPs) demonstrated serine esterases inhibition via scission of the P-C bond as shown in Figure 2.1.A 4. FAPs are known to irreversibly inhibit serine esterases such as acetylcholinesterase16 , neuropathy target esterase, carboxylesterases 17 , etc. Since Pks13-TE contains serine as the nucleophile in the catalytic site, FAPs can be tested against Pks13-TE. Aim 2: Characterize the inhibitory activity of thiophene compounds against Pks13-TE using Isothermal Titration Calorimetry
Zhang, W et al. has Recently shown that thiophene compounds are expected to form non-covalent interactions with Pks13-TE 18. The 4MH-based assay, which is explained in aim 1 will be used to assess the thiophenes inhibitory activity of each thiophene compound that are received from Dr. Steve Sucheck’s …show more content…
Also, the reaction stoichiometry can obtain by the molar ratio at the center of the binding of the isotherm. The heat release per mole of ligand bound, ∆H can be derived directly from the isotherm which reflects the strength of the interactions between pks13-TE and thiophene compounds23-24 . The magnitude of the change in entropy(ΔS) reflects the entropic contributions to the binding 24. The change in heat capacity (ΔCp) suggests the structural information of the Pks13-TE and thiophene complex. The negative ΔCp value indicates an increase in hydrophobic interactions of the complex upon binding. Therefore, using a single ITC experiment can afford the information on binding interactions, nature of the interactions and also the thermodynamic information without using any labels