First-Principles Prediction of the pK_as of Anti-inflammatory Oxicams

Abstract

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.

Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network

“…The difficulty of predicting the oxicam-protein interactions arises for several reasons: the oxicams may exist in several tautomers (22); the two highly coordinated water molecules in the active site are nearly impossible to predict, as the representation and role that water plays in ligand-protein interactions reduces the effectiveness of docking predictions (38); and the recognition of the movement of Leu-531 in COX-2 complexes was only recently reported (36,37). These complex perturbations in the COX-2 active site present an array of computational problems that complicate the prediction of oxicam binding modes.…”

“…1C). The oxicam scaffold exhibits considerable flexibility and exists as several different protonation tautomers through the keto/enol equilibrium (22). Two independent computational studies suggested that oxicam binding to COX-2 might exhibit an inverted mode where the sulfonyl dioxide group in the thiazine interacts with Tyr-385 and Ser-530 as seen with the carboxylic group of diclofenac (23,24).…”

Thermodynamics of chemical reactions with COSMO‐RS: The extreme case of charge separation or recombination

“…Recently, two studies on the application of COSMO‐RS to acid‐base equilibria have been published: In contrast to the already mentioned paper by Coote and coworkers[26] which focuses on one specific chemistry, a benchmark study of Eckert et al covers aqueous dissociation for a broad range of species (94 acids and 75 bases) with the idea to derive linear free energy relationships for a chemistry independent accurate prediction of p K a . It also represents an assessment of advantages and disadvantages of cluster continuum approaches, i.e., the explicit inclusion of few solvent molecules in the quantum chemically treated reactants and products.…”

“…[25] Additionally, a study of Coote and coworkers compares the use of various solvation protocols (also COSMO‐RS applied in the same manner as discussed in the introduction) to aqueous p K a prediction of different acidic sites in drug molecules of the oxicam lead structure. [26] This study already suggests that certain deviations will be encountered when studying protolysis reactions as outlined before: Within the “proton exchange scheme” (i.e., considering a reaction HA 1 + A → A + HA 2 ) involving the same number of ionic species on reactant and product side, it appears possible to predict p K a within 1 unit, whereas deviations are much larger (often 3 p K a units, corresponding to almost 20 kJ/mol) when applying the “direct method” (HA → “H + ” + A), that generates an ion pair from neutral reactant species. However, all these studies only involve aqueous environments.…”

Directed Functionalization of Halophenyl‐2‐oxazolines with TMPMgCl·LiCl

“…The use of computational chemistry to obtain pK a values is an important tool to guide experimental planning. [19] In addition, this strategy has been used to evaluate the influence of C-H acidity on the regioselectivity of metalations of aromatic and heterocyclic substrates. [20,21] The application of isodesmic reactions diminishes issues that may arise when the pK a values are directly calculated by deprotonation reactions.…”