Molecular Docking Study of Conformational Polymorph: Building Block of Crystal Chemistry

Two conformational polymorphs of novel 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-ethoxy]-4,6-dimethyl nicotinonitrile have been developed. The crystal structure of both polymorphs (1a and 1b) seems to be stabilized by weak interactions. A difference was observed in the packing of both polymorphs. Polymorph 1b has a better binding affinity with the cyclooxygenase (COX-2) receptor than the standard (Nimesulide).


Introduction
Polymorphism "Supramolecular isomerism" is pertinent to supramolecular chemistry, and crystal engineering in the same way as isomerization is pertinent to organic molecules. In the simplest way, polymorphism is the ability of molecules to produce more than one crystal structure [1,2], resulted from interplay of kinetic and thermodynamic parameters [3]. The complexities of the organic solid state and especially the differences of intermolecular forces influence crystal packing [4]. Conformational polymorphism will always be a possibility for molecules that have multiple conformational isomers accessible energetically: every different conformation is a different molecular shape and can, in principle, form its own crystalline polymorph (or polymorphs) [5]. Because of the variation in crystallization environment (e.g., temperature, solvent, using of additives, and concentration), the same molecules can pack differently and form different crystal lattices or polymorphs [6][7][8]. As a result, the physical, chemical, and mechanical properties of the crystals can be dramatically affected. Nicotinonitrile-based crystals are highly influenced by and cooperative effects [9]. Self-assemblies of these derivatives are governed by various weak interactions [10][11][12][13][14][15][16][17][18][19][20]. The presence of various weak interactions leads to the development of polymorphism in compounds [21][22][23][24][25]. Polymorphism in organic and inorganic solids can be of crucial importance in the drug design and pharmaceutical industries due to its regulatory action [26][27][28]. Earlier we had studied weak interactions and its polymorphism in 1,3bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane, which was symmetrical dimer [29]. This current study is focused on the pharmaceutical property of dissymmetrical molecule, 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1yl)-ethoxy]-4,6-dimethyl nicotinonitrile, and its polymorphs (1a and 1b).

Instrumentation
. The X-ray diffraction measurements were carried out using a CrysAlis CCD, Oxford diffractometer. The structure was solved by direct methods with the SHELXS-97 program and refined by the full-matrix least squares method on 2 data using the SHELXL-97 program. Molecular graphics: ORTEP; software used to prepare material for publication: MERCURY-3.1. FT-IR spectra were recorded on a VARIAN 3100 FT-IR spectrometer, which was evacuated to avoid water and CO 2 absorptions, at a 2 cm −1 resolution in KBr. The 1H and 13C NMR spectra were recorded on a JEOL AL300 FTNMR spectrometer operating at 300.40 and 75.46 MHz for proton and carbon 13, respectively. The 1H and 13C chemical shifts were measured CDCl 3 solution relative to TMS. The details of the data collection and final refinement parameters are listed in
Weak aromatic interaction (CH⋅ ⋅ ⋅ N, CH⋅ ⋅ ⋅ , and CH⋅ ⋅ ⋅ O interaction) plays an important role in occupying both the polymorphs conformation. A detailed list of their bond lengths and bond angles are summarized in Table 2.
Intermolecular CH⋅ ⋅ ⋅ N (2.573Å, 131.53 ∘ ) and CH⋅ ⋅ ⋅ O (2.425Å, 174.68 ∘ ) interaction stabilized the network of 1a in a symmetrical manner. However, these interactions are absent in polymorph 1b. The major difference observed in the packing diagram of both the polymorphs (Figure 2) is that intermolecular -interaction present between centroid (C13C14C15N3C11C12) and centroid (C4C3C2C1N1C5) of heteroaromatic ring in 1b is crystallized more closely while The Scientific World Journal  in the case of 1a aromatic -interaction is completely absent and packing of this polymorph stabilized by CH⋅ ⋅ ⋅ interaction (Figure 3). Both polymorphs are showing roughness in their morphology due to the formation of zigzag sheets via weak interactions. In other words the crystal packing of molecules seems to achieve maximum crystal density. In the packing of the 1st polymorph 1a, due to CH⋅ ⋅ ⋅ O and CH⋅ ⋅ ⋅ (pibond of CN group) interaction, the molecules linked together and formed a cavity. However, in the case of 1b the ⋅ ⋅ ⋅ and CH⋅ ⋅ ⋅ (pi-bond of CN group) interaction joined the molecules together in packing more tightly and a cavity appears. Presence of different sizes of cavities indicates that both the polymorphs can be used as a host for the different guest molecules. Such kinds of molecular systems will be helpful in many biological systems. Details of intermolecular weak interaction are given in Table 3.
Docking Studies of Synthesized Compound. Firstly, all bound waters, ligands, and cofactors were removed from the proteins. The macromolecule was checked for polar hydrogen; torsion bonds of the inhibitors were selected and defined. Gasteiger charges were computed and the AutoDock atom types were defined using AutoDock 4.2, graphical user interface of AutoDock supplied by MGL Tools [30]. The Lamarckian genetic algorithm (LGA), which is considered one of the best docking methods available in AutoDock [31,32], was employed. This algorithm yields superior docking performance compared to simulated annealing or the simple genetic algorithm and the other search algorithms available  The ability of compound 1a-b to interact with the COX-2 was further assessed by in silico studies with AutoDock ( Figure 4). Results indicate that polymorph 1b shows a better binding effect with COX-2 compared with standard (Nimesulide) than 1a (Table 4). It seems that 1b can further be used as an anti-inflammatory drug.

Conclusion
Weak interactions play an important role in stabilizing the structure of both polymorphs due to which they have different crystal packing. The presence of different sizes of cavities, The Scientific World Journal 5 formed via such weak interactions, plays a crucial role in their biological activity. Polymorph 1b has more binding affinity with COX-2 than polymorph 1a. Polymorph 1b can further be explored for anti-inflammatory activity.