Two Studies of Free Energy in Small Molecule Pharmaceuticals: Polymorph Stability Prediction and Covalent Binding of a Paracetamol Derivative to Human Serum Albumin
Many properties of small organic molecules are dependent on the current crystal packing, or polymorph, of the material, including bioavailability of pharmaceuticals, optical properties of dyes, and charge transport properties of semiconductors. Computational prediction of the most stable crystalline form is done by determining the crystalline form with the lowest relative Gibbs free energy. Effective computational prediction of the most stable polymorph could save significant time and effort in the design of organic solids. In the first study, we demonstrate the use of multistate reweighting methods to determine the most stable polymorph of a crystalline solid across a variety of temperatures and pressures. In order to achieve this, sampling is performed at a selection of temperature and pressure states in the region of interest. Multistate reweighting methods are then employed to determine the reduced free energy differences between T,P states within a polymorph. By combining these reduced free energy differences with a reference Gibbs free energy difference between polymorphs, the relative stability of the polymorphs at the sampled states can be determined and interpolated to create the phase diagram. We have determined the efficiency of using multistate reweighting for this process by determining the relationship between the size of the system and the number of samples required to obtain a constant uncertainty in the results. Using this analysis, we have shown that the numbers of samples needed as the system size increases scales better than the number of molecules in the system.
One pharmaceutical which is known to have multiple stable polymorphs is paracetamol. Understanding the metabolism of paracetamol is important in preventing hepatotoxicity associated with overdose. The primary hepatotoxic metabolic pathway associated with paracetamol involves the adduct, N-acetyl-p-benzoquinone imine (NAPQI). In the second study, the covalent binding of NAPQI with human serum albumin (HSA) was studied. A metadynamics approach was used to study the reaction mechanism of NAPQI with the free cysteine residue of HSA. The free energy along the chosen reaction coordinate was determined and the effect of the protonation state of the sulfur in the free cysteine residue was studied. The protonation state has been shown to affect both the geometry of the relaxed cysteine residue and the free energy along the reaction path.
This is a joint seminar between Oslo and Tromsø in room V205 (Oslo) and ROOM #1.441 (LEVEL 4) Teorifagbygget, House 1 (Tromsø).
The seminars alternate beetween our two Universities and is broadcasted by video to the other place.