Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy

The solubility of organic molecules is of critical importance to the pharmaceutical industry; however, robust computational methods to predict this quantity from first-principles are lacking. Solubility can be computed from a thermodynamic cycle that decomposes standard state solubility into the sum of solid–vapor sublimation and vapor–liquid solvation free energies Δ<i>G</i>_solubility^° = Δ<i>G</i>_sub^° + Δ<i>G</i>_solv^°. Over the past few decades, alchemical simulation methods to compute solvation free energy using classical force fields have become widely used. However, analogous methods for determining the free energy of the sublimation/deposition phase transition are currently limited by the necessity of a priori knowledge of the atomic coordinates of the crystal. Here, we describe progress toward an alternative scheme based on <u>g</u>rowth of the <u>a</u>symmetric <u>u</u>nit into a <u>c</u>rystal via alc<u>he</u>my (GAUCHE). GAUCHE computes deposition free energy Δ<i>G</i>_dep^° = −Δ<i>G</i>_sub^° = −<i>k</i>_B<i>T</i> ln­(<i>V</i>_c/<i>V</i>_g) + Δ<i>G</i>_AU + Δ<i>G</i>_AU→UC as the sum of an entropic term to account for compressing a vapor at 1 M standard state (<i>V</i>_g) into the molar volume of the crystal (<i>V</i>_c), where <i>k</i>_B is Boltzmann’s constant and <i>T</i> is temperature in degrees Kelvin, plus two simulation steps. In the first simulation step, the deposition free energy Δ<i>G</i>_AU for a system composed of only <i>N</i>_AU asymmetric unit (AU) molecule(s) is computed beginning from an arbitrary conformation in vacuum. In the second simulation step, the change in free energy Δ<i>G</i>_AU→UC to expand the asymmetric unit degrees of freedom into a unit cell (UC) composed of <i>N</i>_UC independent molecules is computed. This latter step accounts for the favorable free energy of removing the constraint that every symmetry mate of the asymmetric unit has an identical conformation and intermolecular interactions. The current work is based on NVT simulations, which requires knowledge of the crystal space group and unit cell parameters from experiment, but not a priori knowledge of crystalline atomic coordinates. GAUCHE was applied to 5 organic molecules whose sublimation free energy has been measured experimentally, based on the polarizable AMOEBA force field and more than a microsecond of sampling per compound in the program Force Field X. The mean unsigned and RMS errors were only 1.6 and 1.7 kcal/mol, respectively, which indicates that GAUCHE is capable of accurate prediction of absolute sublimation thermodynamics

Long Directional Interactions (LDIs) in Oligomeric Cofacial Silicon Phthalocyanines and Other Oligomeric and Polymeric Cofacial Phthalocyanines

Crystal structures have been determined for the three-member set of cofacial silicon phthalocyanines, ((<i>n</i>-C₆H₁₃)₃SiO)­[SiPcO]_1–3(Si­(<i>n</i>-C₆H₁₃)₃). The staggering angles between adjacent rings in the dimer and trimer of this set are ∼16°. The interactions leading to these angles have been investigated by the atoms-in-molecules (AIM) and reduced-density-gradient (RDG) methods. The results show that long directional interactions (LDIs) are responsible for these angles. A survey of the staggering angles in various cofacial phthalocyanines described in the literature has revealed the existence of significant LDIs in a number of them. It is apparent that in many cases the ability of LDIs to dominate the forces giving rise to the staggering angles observed in cofacial phthalocyanines depends on their inter-ring separations

Long Directional Interactions (LDIs) in Oligomeric Cofacial Silicon Phthalocyanines and Other Oligomeric and Polymeric Cofacial Phthalocyanines

Crystal structures have been determined for the three-member set of cofacial silicon phthalocyanines, ((<i>n</i>-C₆H₁₃)₃SiO)­[SiPcO]_1–3(Si­(<i>n</i>-C₆H₁₃)₃). The staggering angles between adjacent rings in the dimer and trimer of this set are ∼16°. The interactions leading to these angles have been investigated by the atoms-in-molecules (AIM) and reduced-density-gradient (RDG) methods. The results show that long directional interactions (LDIs) are responsible for these angles. A survey of the staggering angles in various cofacial phthalocyanines described in the literature has revealed the existence of significant LDIs in a number of them. It is apparent that in many cases the ability of LDIs to dominate the forces giving rise to the staggering angles observed in cofacial phthalocyanines depends on their inter-ring separations

Long, Directional Interactions in Cofacial Silicon Phthalocyanine Oligomers

Single crystal structures have been determined for the three cofacial, oxygen-bridged, silicon phthalocyanine oligomers, [((CH₃)₃SiO)₂(CH₃)SiO](SiPcO)_2–4[Si(CH₃)(OSi(CH₃)₃)₂], and for the corresponding monomer. The data for the oligomers give structural parameters for a matching set of three cofacial, oxygen-bridged silicon phthalocyanine oligomers for the first time. The staggering angles between the six adjacent cofacial ring pairs in the three oligomers are not in a random distribution nor in a cluster at the intuitively expected angle of 45° but rather are in two clusters, one at an angle of 15° and the other at an angle of 41°. These two clusters lead to the conclusion that long, directional interactions (LDI) exist between the adjacent ring pairs. An understanding of these interactions is provided by atoms-in-molecules (AIM) and reduced-density-gradient (RDG) studies. A survey of the staggering angles in other single-atom-bridged, cofacial phthalocyanine oligomers provides further evidence for the existence of LDI between cofacial phthalocyanine ring pairs in single-atom-bridged phthalocyanine oligomers

Long, Directional Interactions in Cofacial Silicon Phthalocyanine Oligomers

Single crystal structures have been determined for the three cofacial, oxygen-bridged, silicon phthalocyanine oligomers, [((CH₃)₃SiO)₂(CH₃)SiO](SiPcO)_2–4[Si(CH₃)(OSi(CH₃)₃)₂], and for the corresponding monomer. The data for the oligomers give structural parameters for a matching set of three cofacial, oxygen-bridged silicon phthalocyanine oligomers for the first time. The staggering angles between the six adjacent cofacial ring pairs in the three oligomers are not in a random distribution nor in a cluster at the intuitively expected angle of 45° but rather are in two clusters, one at an angle of 15° and the other at an angle of 41°. These two clusters lead to the conclusion that long, directional interactions (LDI) exist between the adjacent ring pairs. An understanding of these interactions is provided by atoms-in-molecules (AIM) and reduced-density-gradient (RDG) studies. A survey of the staggering angles in other single-atom-bridged, cofacial phthalocyanine oligomers provides further evidence for the existence of LDI between cofacial phthalocyanine ring pairs in single-atom-bridged phthalocyanine oligomers

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV

Benzimidazole <b>1</b> is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of <b>1</b>, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug <b>2</b>. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of <b>1</b> compared to dosing the parent in multiple species. The prodrug <b>2</b> has improved aqueous solubility, simplifying both intravenous and oral formulation