Polymorphic Forms of Valinomycin Investigated by NMR Crystallography

Abstract

A dodecadepsipeptide valinomycin (VLM) has been most recently reported to be a potential anti-coronavirus drug that could be efficiently produced on a large scale. It is thus of importance to study solid-phase forms of VLM in order to be able to ensure its polymorphic purity in drug formulations. The previously available solid-state NMR (SSNMR) data are combined with the plane-wave DFT computations in the NMR crystallography framework. Structural/spectroscopical predictions (the PBE functional/GIPAW method) are obtained to characterize four polymorphs of VLM. Interactions which confer a conformational stability to VLM molecules in these crystalline forms are described in detail. The way how various structural factors affect the values of SSNMR parameters is thoroughly analyzed, and several SSNMR markers of the respective VLM polymorphs are identified. The markers are connected to hydrogen bonding effects upon the corresponding (13C/15N/1H) isotropic chemical shifts of (CO, Namid, Hamid, Hα) VLM backbone nuclei. These results are expected to be crucial for polymorph control of VLM and in probing its interactions in dosage forms.

The Physical Chemistry and Chemical Physics (PCCP) Section of the International Journal of Molecular Sciences in Its Publications: The First 300 Thematic Articles in the First 3 Years

“…This area is the largest in terms of the number of related publications and includes 91 articles, namely [ 1 , 2 , 3 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 ,…”

“…The last one seems to be the most detailed, and it is precisely this that we will try to implement in the course of our narrative. As it should be expected, a priori, most of the publications in this direction are devoted to organic compounds, and primarily organic molecules; these include, with varying degrees of correctness, publications [ 1 , 2 , 3 , 102 , 103 , 104 , 106 , 108 , 112 , 117 , 118 , 119 , 121 , 124 , 127 , 128 , 130 , 131 , 132 , 133 , 135 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 146 , 147 , 148 , 151 , 153 , 154 , 156 , 157 , 164 , 165 , 166 , 168 , 171 , 172 , 174 , 176 , 178 , 180 , 183 , 185 , 186 ]. Much less space is occupied by the works related to polymeric (in fact, to a high molecular weight) compounds [ 113 , …”

“…In this regard, a review [ 141 ] devoted to porphyrin nanoparticles for the phototherapeutic treatment of oncological diseases is of considerable interest. (Since we are talking about such an important problem of modern human civilization as the treatment and prevention of various diseases, it is worth mentioning article [ 151 ], in which polymorphic forms of valinomycin were obtained and characterized by various methods, which seem to be promising for the treatment of COVID-19). In addition to the three reviews named above, others are presented in this thematic area.…”

The Nonribosomal Peptide Valinomycin: From Discovery to Bioactivity and Biosynthesis

“…Importantly, crystal structures of valinomycin have been known for a long time [ 21 , 22 ]. Its polymorphism would have to be taken into account in a possible manufacturing of drug formulations, as discussed in a report [ 23 ]. Previous studies on the mechanism of action of valinomycin have demonstrated that, due to the hydrophobic surface of valinomycin, the valinomycin-K + complex can be incorporated into biological bilayer membranes and allows the transportation of K + through the membrane to destroy the normal K + gradient across the membrane, thus dissipating the membrane potential, and as a result kills the cells [ 24 , 25 , 26 , 27 , 28 , 29 ].…”

Modeling the Structure of Crystalline Alamethicin and Its NMR Chemical Shift Tensors

“…X-ray diffraction (XRD) and SSNMR experimental studies can be usefully complemented by plane-wave density-functional theory (PW DFT)-based calculations of periodic solids to accurately characterize structures and SSNMR spectral parameters [24]. The second area concerns well-known improvements in related software and hardware, which make it possible to routinely compute the properties of structures with a crystal unit-cell volume exceeding five nm 3 (if the number of symmetry-independent molecules in such a unit cell is not excessively large) [25]. The aforementioned development enabled us to model crystalline ALM.…”