Propoxazepam conformation and its orientation in the GABAA-receptor binding site

V. B. Larionov, M. Ya. Golovenko, A. S. Reder

Abstract


Introduction. One of 1.4-benzodiazepine 3-alcoxy derivatives – propoxazepam, possessing high analgetic action, also effectively suppressed different experimental seizures types. Unexpected combination of pharmacological spectrum components suggests its different binding sites of GABAA receptor.
The aim of the work was to determine the geometry of the ligand-receptor complexes of GABA-RC using experimental data of the propoxazepam conformation and calculated data for the three-dimensional structure of the ligandbinding site and subsequent docking to characterize its binding to this receptor.
Materials and methods. X-ray diffraction studies of the compound were performed using Xcalibur 3 single crystal X-ray diffractometer. Calculation of the molecular docking parameters was performed using the iGEMDOCK v2.1 program for the GABA receptor (GABA (A) R-beta3 homopentamer, 4COF), the molecular structures of propoxazepam conformers were prepared using ChemAxon (MarvinSketch 17.11.0).
Results and discussion. Based on the X-ray diffraction analysis, the coordinates of the atoms, bond lengths and valence angles in the propoxazepam molecule were calculated, it is found that it form crystallographic twins as racemate. The molecular docking method showed that propoxazepam several binding sites with the energy of complex formation from -78.64 to -85.29 kcal/mol exist on the isolated site of the GABA-receptor.
Conclusions. The highest contribution to the formation of the bond of the complex is carried out by residues of polar amino acids (serine, asparagine, methionine and arginine in polar binding sub-center). However, also for individual conformers, aromatic amino acids, predominantly phenylalanine (Phe-31, Ala-135 – hydrophobic binding sub-center) make a significant contribution.


Keywords


propoxazepam; X-ray diffraction; docking; GABAA-recepto

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References


Whiting, P. J. (2003). GABA–A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discovery Today, 8 (10), 445–450. doi: 10.1016/s1359–6446(03)02703–x

Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., Sperk, G. (2000). GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience, 101 (4), 815–850. doi: 10.1016/s0306–4522(00)00442–5

Clayton, T., Chen, J., Ernst, M., Richter, L., Cromer, B., Morton, C., Cook, J. (2007). An updated unified pharmacophore model of the benzodiazepine binding site on γ – aminobutyric acid a receptors: correlation with comparative models. Current Medicinal Chemistry, 14 (26), 2755–2775. doi: 10.2174/092986707782360097

Olsen, R. W., Sieghart, W. (2009). GABAA receptors: Subtypes provide diversity of function and pharmacology. Neuropharmacology, 56 (1), 141–148. doi: 10.1016/j.neuropharm.2008.07.045

Pavlovsky, V. I., Tsymbalyuk, O. V., Martynyuk, V. S., Kabanova, T. A., Semenishyna, E. A., Khalimova, E. I., Andronati, S. A. (2013). Analgesic Effects of 3– Substituted Derivatives of 1,4–Benzodiazepines and their Possible Mechanisms. Neurophysiology, 45 (5–6), 427–432. doi: 10.1007/s11062–013–9389–y

Voloshchuk, N. I., Reder, A. S., Golovenko, N. Ya. et al. (2017). Farmakologicheskaia lekarstvennaia toxicologiia, 1 (52), 3–11.

Blommel, M. L., Blommel, A. L. (2007). Pregabalin: An antiepileptic agent useful for neuropathic pain. American Journal of Health–System Pharmacy, 64 (14), 1475–1482. doi: 10.2146/ajhp060371

Taylor, C. P., Gee, N. S., Su, T.–Z., Kocsis, J. D., Welty, D. F., Brown, J. P., Singh, L. (1998). A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Research, 29 (3), 233–249. doi: 10.1016/s0920–1211(97)00084–3

Golovenko, N. Ya., Larionov, V. B., Reder, A. S. et al. (2016) Zhurnal akademii meditcinskikh nauk Ukrainy, 3–4, 251–260.

Golovenko, M. Y., Reder, A. S., Larionov, V. B., Valivodz`, I. P. (2017). The effect of propoxazepam on development of thiosemicarbazide–induced GABA–deficient seizures in mice. Klìnìčna Farmacìâ, 21 (2), 34–40. doi: 10.24959/cphj.17.1419

Sheldrick, G. M. (2007). A short history of SHELX. Acta Crystallographica Section A Foundations of Crystallography, 64 (1), 112–122. doi: 10.1107/s0108767307043930


GOST Style Citations


1. Whiting, P. J. GABA–A receptor subtypes in the brain : a paradigm for CNS drug discovery? / P. J. Whiting // Drug Discov Today. – 2003. – Vol. 8, Issue 10. – P. 445–450. doi: 10.1016/s1359–6446(03)02703–x

2. GABA(A) receptors : immunocytochemical distribution of 13 subunits in the adult rat brain / S. Pirker, C. Schwarzer, A. Wieselthaler et al. //Neurosci. – 2000. – Vol. 101, Issue 4. – P. 815–850. doi: 10.1016/s0306–4522(00)00442–5

3. An updated unified pharmacophore model of the benzodiazepine binding site on γ –aminobutyric acid a receptors : correlation with comparative models / T. Clayton, J. L. Chen, M. Ernst et al. // Current Med. Chem. – 2007. – Vol. 14, Issue 26. – P. 2755–2775. doi: 10.2174/092986707782360097

4. Olsen, R. W. GABA A receptors : subtypes provide.diversity of function and pharmacology / R. W. Olsen, W. Sieghart // Neuropharmacol. – 2009. – Vol. 56, Issue 1. – Р. 141–148. doi: 10.1016/j.neuropharm.2008.07.045

5. Analgesic Effects of 3–substituted derivatives of 1,4–benzodiazepines and their possible mechanisms / V. I. Pavlovsky, O. V. Tsymbalyuk, V. S. Martynyuk et al. // Neurophysiol. – 2003. – Vol. 45, Issue 5/6. – P. 427–432. doi: 10.1007/s11062–013–9389–y

6. Фармакологический анализ нейрохимических антиноцицептивных механизмов действия пропоксазепама / Н. И. Волощук, А. С. Редер, Н. Я. Головенко и др. // Фармакол. лек. токсикол. – 2017. – № 1 (52). – С. 3–11.

7. Blommel, M. L. Pregabalin : An antiepileptic agent useful for neuropathic pain / M. L. Blommel, A. L. Blommel // Am. J. Health–Syst Pharm. – 2007. – Vol. 64, Issue 14. – P. 1475–1482. doi: 10.2146/ajhp060371

8. A summary of mechanistic hypotheses of gabapentin pharmacology / C. P. Taylor, N. S. Gee, Su Ti–Zhi et al. // Epilepsy Res. – 1998. – Vol. 29, Issue 3. – P. 233–249. doi: 10.1016/s0920–1211(97)00084–3

9. Активация ГАМКергической системы пропилоксипроизводным 1,4–бенздиазепина на моделях нейропатической боли и судорог, индуцированных коразолом / Н. Я. Головенко, В. Б. Ларионов, А. С. Редер и др. // Журн. НАМН Украины. – 2016. – № 3–4. – С. 251–260.

10. Propoxazepam influence on thiosemicarbazide–induced GABA–deficient seizures development in mice / M. Ya. Golovenko, A. S. Reder, V. B. Larionov, I. P. Valivodz` // Клінічна фармація. – 2017. – Т. 21, № 2. – Р. 34–40. doi: 10.24959/cphj.17.1419

11. Sheldrick, G. M. A short history of SHELX / G. M. Sheldrick // Acta Crystallographica Section A Foundations of Crystallography. – 2007. – Vol. 64, Issue 1. – P. 112–122. doi: 10.1107/s0108767307043930

12. Yang, J.–M. GEMDOCK : A generic evolutionary method for molecular docking / J.–M. Yang, C.–C. Chen // Proteins : Structure, Function and Bioinformatics. – 2004. – Vol. 55, Issue 2. – P. 288–304. doi: 10.1002/prot.20035

13. Consensus Scoring Criteria for Improving Enrichment in Virtual Screening / J.–M. Yang, Y.–F. Chen, T.–W. Shen et al. // J. Chem. Inform and Modeling. – 2005. – Vol. 45, Issue 4. – P. 1134–1146. doi: 10.1021/ci050034w

14. Miller, P. S. Crystal structure of a human GABAA receptor / P. S. Miller, A. Radu Aricescu // Nature. – 2014. – Vol. 512, Issue 7514. –P. 270–275. doi: 10.1038/nature13293





DOI: https://doi.org/10.24959/ubphj.18.150

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