Electrostatic properties of nine fluoroquinoloneantibiotics derived directly from their crystal structure refinements

Abstract

This article discusses the relevance of the similarity of the molecular electrostatic potential for rational drug design and optimization of lead structures on the basis of a comparison of nine fluoroquinolone antibiotics. Molecular electrostatic potentials and dipole moments were calculated directly from the electron-density distribution after crystal structure refinement with invarioms, theoretical nonspherical scattering factors. Deposited, newly determined and re-measured single-crystal diffraction data of varying quality were evaluated in this manner. An in silico validation procedure for invariom database entries is presented. Despite differences in their substitution pattern, molecular electrostatic potentials for molecules with the same protonation states show a striking degree of similarity for the whole group of compounds studied. The rapid calculation of electrostatic potentials directly from the invariom database makes the procedure suitable for high-throughput screening.

Can ion mobility mass spectrometry and density functional theory help elucidate protonation sites in 'small' molecules?

“…To further understand the likely protonation sites in norfloxacin (Scheme ) DFT calculations were undertaken using an initial geometry based on a recently obtained crystal structure and are collected in Table . The geometry was optimised at the B3LYP/6‐311++G(d,p) level.…”

“…All calculations were performed using the 6‐311++G(d,p) basis set, which was considered to be large enough to provide reliable relative energies. The initial model for the geometry optimisation of norfloxacin was obtained from the most recent crystal structure . Initial models for each of the protonated derivatives were constructed by placing a hydrogen atom at a distance of 1 Å from each putative protonation site, followed by geometry optimisation.…”

Probing Weak Intermolecular Interactions by Using the Invariom Approach: A Comparative Study ofs‐Tetrazine

“…They were devised to replace an independent atom model (IAM)3, 4 by using database entries of multipolar parameters obtained within the Hansen–Coppens aspherical‐atom formalism5 from X‐ray measurements of high quality6 or from quantum chemical calculations 2. 7 As well as taking as less time than IAM to employ,8, 9 their use allows reaching the accuracy of conventional multipole refinement against high‐resolution data 8. If the latter is somehow not an option, transferred multipolar modeling is a good alternative towards electron density distribution and does not require time‐ and recourse‐consuming experimental techniques and computations, because it is based on a database approach.…”

“…Those include a more reliable absolute structure determination for light‐atom compounds,13 charge density studies from low (normal) resolution datasets,9, 14, 15 only collectible with copper radiation,4 and of larger molecules with poor reflective power,16 identification and treatment of a disorder,17 and so on. Thus, being an extremely promising approach, it can even use other starting geometries than from X‐ray diffraction, for example, those obtained from quantum chemistry or NMR spectroscopy 8…”

Molecular Electrostatic Potentials from Invariom Point Charges

“…In this branch of crystallography,t he focus is on the molecular charge density distribution (CDD) from precise high-resolution (sinV/ l !1.0 o rd 0.5 ) X-ray diffraction data. [49] Moreover,t he experimental ESP corresponds to am olecule in the crystal, which, as comparison to its gas-phase counterpart shows, can lead to additional polarization. Here due caution has to be exercised because accurate ESPs can only be obtained for non-disordered compounds, given that minor disorder can already lead to misleading results.…”