Progress in the Understanding of Drug–Receptor Interactions, Part 2: Experimental and Theoretical Electrostatic Moments and Interaction Energies of an Angiotensin II Receptor Antagonist (C₃₀H₃₀N₆O₃S)

Abstract

A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.

Anharmonic Thermal Motion Modelling in the Experimental XRD Charge Density Determination of 1-Methyluracil at T = 23 K

“…As pointed out in our previous work [ 58 , 65 ], Stewart atoms extend to infinity and overlap with each other in the same way as in other so-called “fuzzy” partitionings of the EDD (e.g., Becke [ 66 ] and Hirshfeld’s stockholder [ 67 , 68 ] schemes). As fuzzy molecules have boundaries at infinity, the moments reported in Table 5 refer to a molecule removed from the crystal and are directly comparable with the theoretically calculated values.…”

Contributions of charge-density research to medicinal chemistry

“…Because such ideal situations are unavailable, it is constructive to first study separately a single, active small-molecule pharmaceutical ingredient. Many such studies have been performed (Howard et al, 1995;Flaig et al, 2001;Hibbs et al, 2003;Ghermani et al, 2004;Destro et al, 2005;Soave et al, 2007;Rajalakshmi et al, 2014), more recently also on a pair of polymorphs (Overgaard & Hibbs, 2004;Nelyubina et al, 2010), a series of pharmaceutically active molecules (Zhurova et al, 2006;Parrish et al, 2006;Yearley et al, 2007;Zhurova et al, 2009;Grabowsky et al, 2008) and anion-receptor complexes (Kirby et al, 2014) in comparative CD studies, to give just a few examples. For further illustration a study on two penicillin molecules, one active and one inactive (Wagner et al, 2004), will now be discussed in slightly more detail.…”

“…Another similarity is that the interaction energy is a feature of the crystal packing, and is an energy difference. Many studies have been carried out to obtain interaction energies in small-molecule systems (Spackman & Weber, 1988;Abramov et al, 2000a,b;Li et al, 2002;Soave et al, 2007;Bouhmaida et al, 2009). These pivotal studies provided very useful experiences, including an assessment of accuracy and the EP/MM approach currently seems closest to a user-friendly implementation of the concepts involved.…”

Progress in the Understanding of the Key Pharmacophoric Features of the Antimalarial Drug Dihydroartemisinin: An Experimental and Theoretical Charge Density Study

“…In accordance with IUPAC, [33] a pharmacophore is defined as "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biology-A C H T U N G T R E N N U N G ical target and to trigger (or block) its biological response". From this viewpoint, the principle of electrostatic complementarity plays a key role [34] in determining how different molecules interact (and possibly react) with each other. Indeed, all the effects of molecular self-recognition are present in a crystalline environment, and can be expected to be comparable in size with those exploited between the guest molecule and its host.…”