Rentiapril

Organic mols. crystallize in manifold structures.The last few decades have seen the rise of high-resolution X-ray diffraction techniques that make the structures of even the most complex crystals easily accessible.Still, an intrinsic challenge lies in assigning hydrogen atoms' positions from X-ray experiments alone.Quantum chem. plays a fruitful, complementary role here, and so ab initio optimization techniques for organic crystals are on the rise as well.In this context, the authors evaluate a popular ab initio strategy based on plane-wave d.-functional computations, namely, selectively relaxing H positions in an otherwise fixed cell.Our data show that such-optimized C-H, N-H, O-H, and B-H bond lengths coincide well with results from neutron diffraction-the exptl. technique that sets the gold standard for H positions in mol. crystals but which is far less easily available.The authors justified the use of a quantum-chem. aide with a broad variety of possible applications.

The metallopeptidase Angiotensin Converting Enzyme (ACE) is an important drug target for the treatment of hypertension, heart, kidney, and lung disease. Recently, a close and unique human ACE homologue termed ACE2 has been identified and found to be an interesting new cardiorenal disease target. With the recently resolved inhibitor-bound ACE2 crystal structure available, we have attempted a structure-based approach to identify novel potent and selective inhibitors. Computational approaches focus on pharmacophore-based virtual screening of large compound databases. Selectivity was ensured by initial screening for ACE inhibitors within an internal database and the Derwent World Drug Index, which could be reduced to zero false positives and 0.1% hit rate, respectively. An average hit reduction of 0.44% was achieved with a five feature hypothesis, searching approximately 3.8 million compounds from various commercial databases. Seventeen compounds were selected based on high fit values as well as diverse structure and subjected to experimental validation in a bioassay. We show that all compounds displayed an inhibitory effect on ACE2 activity, the six most promising candidates exhibiting IC50 values in the range of 62-179 microM.