Pharmacophore Fragment-Based Prediction and Gas-Phase ab Initio Optimization of Carvedilol Conformations

This current communication gives the results of a novel computational molecular method of selecting, from a vast number of possible conformations, the dominant low-energy states of a large molecule by dividing it into separately analyzable structure−activity fragments. Carvedilol is a cardiovascular drug of proven efficacy with multiple molecular targets: it acts as a nonselective β-adrenoceptor (β 1 and β 2 ) and selective α 1 -adrenoceptor antagonist, an antioxidant able to reduce reactive oxygen species (ROS)-mediated oxidative stress, a beneficial modulator of cardiac electrophysiological properties (K + and Ca 2+ ion channels), a multifaceted cardioprotector, and novel antifibrillar agent able to inhibit amyloid-beta (Aβ) fibril formation. Given carvedilol's varied pharmacodynamic profiles, and the fact that a thorough analysis of its potential energy hypersurface (PEHS) has not yet been performed, an original molecular fragmentation method was developed to reveal carvedilol's low-energy states, to divulge their relevance to its biological activity. Multidimensional conformational analysis (MDCA) leads to a total of 177 147 (3 11 ) conformational possibilities, whereas fragmentation studies predict 240 gas-phase conformations. Structural predictions were tested on protonated R -carvedilol with gas-phase molecular orbital (MO) computations of PEHS minima at the restricted Hartree−Fock (RHF) (RHF/3-21G) level of theory, using the Gaussian 98 software program. Computation of the 240 predicted (input) carvedilol conformations revealed 121 converged (i.e., fully optimized) structures, of which nine possessed a conformer relative energy of <4 kcal/mol. Seven of these nine conformers possess a unique “tetra-centric” (four-centered) spiro-type structure that is composed of two rings (six- and eight-membered) enclosed by two O···H−N hydrogen bonds (H-bonds) that are connected via the protonated N atom in the side chain of carvedilol; this conformation is largely determined by the carbazole-containing pharmacophore (Fragment A) of carvedilol. In regard to the utility of the rational molecular fragmentation method used to predict and optimize the carvedilol structures, it is determined that 8 of the 11 torsional angles were accurately predicted (72.7%), according to torsional angle conformation distribution. The strength of this fragmentation method relies on full MDCA optimization of the individual fragments, which are then used to predict the carvedilol conformations. As such, the predicted inputs possess an inherent degree of energy minimization and, thus, are able to provide a better hypothesis of relevant sections of the carvedilol surface versus a random sampling of the PEHS. The elucidation of carvedilol's conformational identity greatly aids the full molecular understanding of carvedilol's adrenoceptor binding structure and carvedilol's involvement, at the molecular level, in ameliorating pathological states such as oxidative stress and Alzheimer's disease.

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