IN SILICO DRUG DESIGNING AND DOCKING STUDY FOR NOVEL ANTIHYPERTENSIVE HYBRIDS
Main Article Content
Keywords
Cardiovascular hybrid drugs, thiazolidine-4-one, docking study, ADMET
Abstract
This work aimed to conduct docking and novel antihypertensive agents having three moieties of different mechanisms of action; one of which is NO donor, which is reported to possess vasodilator activity and thiazolidine-4-one is reported to possess antiarrhythmic activity. These two moieties were clubbed through β-blocking moiety. 9 derivatives of general formula 2-(4-(2-hydroxy -3-(4-oxo-2-phenylimino) thizolidin-3-yl) phenyl)-2-oxoethyl nitrate were selected. Schrodinger was used to perform molecular docking using Maestro Glide. All compounds were constructed using Maestro build panels and then optimized for lower energy conformers using Ligprep (Schrodinger, LLC). With the help of protein preparation wizards, the protein X-ray crystal structure (PDB ID:6M7H) was obtained from the protein data bank and made docking-ready. When compared to amlodipine, SD7, SD3, SD9, SD4, and SD8 show good binding patterns and good scores. Of all the molecules, SD7 has the highest docking score of -9.177 kcal mol−1.
References
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20. Hadizadeh F, Hassanabad ZF, Bamshad M, Poorsoghat H, Hassanabad MF. Synthesis and antihypertensive activity of new 1, 4-dihydropyridines Indian J. Chem., 41B, 2343-2346.
21. Jain SK, Mishra P. Preparation and evaluation of some 1, 3, 4-thiadiazoles as diuretic agents Indian J. Chem. 43B, 184-188.
22. Kheli, S., Leclerer, G., 1995. Synthesis and pharmacological activities of 3, 7-sulfonylurea-1, 2, 4-benzothiadiazole-1, 1-dioxides on rat aorta. Bioorg. Med. Chem. 3, 495-503.
23. Smith, R., Timmermans, W., Pieter, B., 1996. Antihypertensive agents. Wolf, A., Berger’s Medicinal Chemistry and Drug Descovery. Fifth ed. New York, pp 265-314.
24. Acharjee S, Bothara KG, Bhandari SV, Maity TK. Design, synthesis and pharmacological screening of hybrid molecules as antihypertensives. Medicinal Chemistry Research. 2011 Jul;20:705-13.
25. Visentin S, Rolando B, Di Stilo A, Fruttero R, Novara M, Carbone E, Roussel C, Vanthuyne N, Gasco A. New 1, 4-dihydropyridines endowed with NO-donor and calcium channel agonist properties. Journal of medicinal chemistry. 2004 May 6;47(10):2688-93
26. Waring WS, Webb DJ. Is there a need for novel antihypertensive therapies Drug Discovery Today: Therapeutic Strategies. 2004 Oct 1;1(2):143-8.
27. Takkar P, Singh B, Pani B, Kumar R. Design, synthesis and in silico evaluation of newer 1, 4-dihydropyridine based amlodipine bio-isosteres as promising antihypertensive agents. RSC advances. 2023;13(48):34239-48.
28. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry. 2010 Jan 30;31(2):455-61.
29. Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD, Salmon JK. Scalable algorithms for molecular dynamics simulations on commodity clusters. In Proceedings of the 2006 ACM/IEEE Conference on Supercomputing 2006 Nov 11 (pp. 84-es).
30. Doherty W, Adler N, Knox A, Nolan D, McGouran J, Nikalje AP, Lokwani D, Sarkate A, Evans P. Synthesis and evaluation of 1, 2, 3‐triazole‐containing vinyl and allyl sulfones as anti‐trypanosomal agents. European Journal of Organic Chemistry. 2017 Jan 3;2017(1):175-85.
31. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of medicinal chemistry. 2004 Mar 25;47(7):1739-49.
32. Karnik KS, Narula IS, Sarkate AP, Wakte PS. Auto QSAR fast approach for creation and application of QSAR models through automation. Chemistry Select. 2020 May 22;5(19):5756-62.
2. Almansa C, Gómez LA, Cavalcanti FL, de Arriba AF, Rodríguez R, Carceller E, García-Rafanell J, Forn J. Diphenylpropionic acids as new AT1 selective angiotensin II antagonists. Journal of medicinal chemistry. 1996 May 24;39(11):2197-206.
3. Mobine HR, Baker AB, Wang L, Wakimoto H, Jacobsen KC, Seidman CE, Seidman JG, Edelman ER. Pheochromocytoma-induced cardiomyopathy is modulated by the synergistic effects of cell-secreted factors. Circulation: Heart Failure. 2009 Mar 1;2(2):121-8.
4. Bertram G Katzung Ka. Basic & clinical pharmacology. EGC. sixth ed. Principal & Hall International edition, pp 166.
5. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. Jama. 2003 May 21;289(19):2560-71.
6. Bhandari SV, Bothara KG, Patil AA, Chitre TS, Sarkate AP, Gore ST, Dangre SC, Khachane CV. Design, synthesis, and pharmacological screening of novel antihypertensive agents using a hybrid approach. Bioorganic & medicinal chemistry. 2009 Jan 1;17(1):390-400.
7. Huang YC, Wu BN, Yeh JL, Chen SJ, Liang JC, Lo YC, Chen J. A new aspect of view in synthesizing new type β-adrenoceptor blockers with ancillary antioxidant activities. Bioorganic & medicinal chemistry. 2001 Jul 1;9(7):1739-46.
8. Liang JC, Yeh JL, Wang CS, Liou SF, Tsai CH, Chen J. The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display α-/β-Adrenoceptor antagonist and long-acting antihypertensive activities. Bioorganic & medicinal chemistry. 2002 Mar 1;10(3):719-30.
9. Boschi D, Cena C, Di Stilo A, Fruttero R, Gasco A. Nicorandil analogs containing NO-donor furoxans and related furazans. Bioorganic & medicinal chemistry. 2000 Jul 1;8(7):1727-32.
10. Breschi MC, Calderone V, Digiacomo M, Martelli A, Martinotti E, Minutolo F, Rapposelli S, Balsamo A. NO-sartans: a new class of pharmacodynamic hybrids as cardiovascular drugs. Journal of medicinal chemistry. 2004 Nov 4;47(23):5597-600.
11. Campiani G, Fiorini I, De Filippis MP, Ciani SM, Garofalo A, Nacci V, Giorgi G, Sega A, Botta M, Chiarini A, Budriesi R. Cardiovascular characterization of pyrrolo benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers. Journal of medicinal chemistry. 1996 Jul 19;39(15):2922-38.
12. Mehanna AS, Kim JY. Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers. Bioorganic & medicinal chemistry. 2005 Jul 1;13(13):4323-31.
13. Nguyen JT, Velázquez CA, Knaus EE. Hantzsch 1, 4-dihydropyridines containing a diazen-1-ium-1, 2-diolate nitric oxide donor moiety to study calcium channel antagonist structure–activity relationships and nitric oxide release. Bioorganic & medicinal chemistry. 2005 Mar 1;13(5):1725-38.
14. Perez M, Pauwels PJ, Pallard-Sigogneau I, Fourrier C, Chopin P, Palmier C, Colovray V, Halazy S. Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors. Bioorganic & medicinal chemistry letters. 1998 Dec 1;8(23):3423-8.
15. Natale NR, Rogers ME, Staples R, Triggle DJ, Rutledge A. Lipophilic 4-Isoxazolyl-1, 4-dihydropyridines: Synthesis and Structure− Activity Relationships. Journal of medicinal chemistry. 1999 Aug 12;42(16):3087-93.
16. Yagupolskii LM, Antepohl W, Artunc F, Handrock R, Klebanov BM, Maletina II, Marxen B, Petko KI, Quast U, Vogt A, Weiss C. Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties. Journal of medicinal chemistry. 1999 Dec 16;42(25):5266-71.
17. Ferrarini PL, Mori C, Primofiore G, Da Settimo A, Breschi MC, Martinotti E, Nieri PA, Ciucci MA. Synthesis and β-blocking activity of (E)-and (Z)-iminoethers of 1, 8-naphthyridine. Potential antihypertensive agents. 4. European Journal of Medicinal Chemistry. 1990 Jul 1;25(6):489-96.
18. Fisher LE, Rosenkranz RP, Clark RD, Muchowski JM, McClelland DL, Michel A, Caroon JM, Galeazzi E, Eglen R, Whiting RL. N, N-6-bis-[2-(3, 4-dihydroxybenzyl) pyrrolidinyl] hexane, a potent, selective, orally active dopamine analog with hypotensive and diuretic activity. Bioorganic & Medicinal Chemistry Letters. 1995 Oct 19;5(20):2371-6.
19. Hanft G, Kolassa N. Urapidil and some analogs with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT 1A subtype and α 1-adrenoceptor binding sites. Naunyn-Schmiedeberg's archives of pharmacology. 1987 Dec;336:597-601.
20. Hadizadeh F, Hassanabad ZF, Bamshad M, Poorsoghat H, Hassanabad MF. Synthesis and antihypertensive activity of new 1, 4-dihydropyridines Indian J. Chem., 41B, 2343-2346.
21. Jain SK, Mishra P. Preparation and evaluation of some 1, 3, 4-thiadiazoles as diuretic agents Indian J. Chem. 43B, 184-188.
22. Kheli, S., Leclerer, G., 1995. Synthesis and pharmacological activities of 3, 7-sulfonylurea-1, 2, 4-benzothiadiazole-1, 1-dioxides on rat aorta. Bioorg. Med. Chem. 3, 495-503.
23. Smith, R., Timmermans, W., Pieter, B., 1996. Antihypertensive agents. Wolf, A., Berger’s Medicinal Chemistry and Drug Descovery. Fifth ed. New York, pp 265-314.
24. Acharjee S, Bothara KG, Bhandari SV, Maity TK. Design, synthesis and pharmacological screening of hybrid molecules as antihypertensives. Medicinal Chemistry Research. 2011 Jul;20:705-13.
25. Visentin S, Rolando B, Di Stilo A, Fruttero R, Novara M, Carbone E, Roussel C, Vanthuyne N, Gasco A. New 1, 4-dihydropyridines endowed with NO-donor and calcium channel agonist properties. Journal of medicinal chemistry. 2004 May 6;47(10):2688-93
26. Waring WS, Webb DJ. Is there a need for novel antihypertensive therapies Drug Discovery Today: Therapeutic Strategies. 2004 Oct 1;1(2):143-8.
27. Takkar P, Singh B, Pani B, Kumar R. Design, synthesis and in silico evaluation of newer 1, 4-dihydropyridine based amlodipine bio-isosteres as promising antihypertensive agents. RSC advances. 2023;13(48):34239-48.
28. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry. 2010 Jan 30;31(2):455-61.
29. Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepeis JL, Kolossvary I, Moraes MA, Sacerdoti FD, Salmon JK. Scalable algorithms for molecular dynamics simulations on commodity clusters. In Proceedings of the 2006 ACM/IEEE Conference on Supercomputing 2006 Nov 11 (pp. 84-es).
30. Doherty W, Adler N, Knox A, Nolan D, McGouran J, Nikalje AP, Lokwani D, Sarkate A, Evans P. Synthesis and evaluation of 1, 2, 3‐triazole‐containing vinyl and allyl sulfones as anti‐trypanosomal agents. European Journal of Organic Chemistry. 2017 Jan 3;2017(1):175-85.
31. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of medicinal chemistry. 2004 Mar 25;47(7):1739-49.
32. Karnik KS, Narula IS, Sarkate AP, Wakte PS. Auto QSAR fast approach for creation and application of QSAR models through automation. Chemistry Select. 2020 May 22;5(19):5756-62.
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Apr 16, 2022
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Ashwini A. Bhosale, Ganesh S. Andhale, & Rajesh B. Patil. (2022). IN SILICO DRUG DESIGNING AND DOCKING STUDY FOR NOVEL ANTIHYPERTENSIVE HYBRIDS . Journal of Population Therapeutics and Clinical Pharmacology, 29(04), 1675–1683. https://doi.org/10.53555/jptcp.v29i04.4828
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Author Biographies
Ashwini A. Bhosale
Department of Pharmaceutical Chemistry, Sinhgad Technical Education Society, Sinhgad College of Pharmacy, Vadgaon(Bk), Pune 411041, Maharashtra, India.
Ganesh S. Andhale
Department of Pharmaceutical Chemistry, Alard College of Pharmacy, Marunje, Hinjwadi, Pune-411028, Maharashtra, India.
Rajesh B. Patil
Department of Pharmaceutical Chemistry, Sinhgad Technical Education Society, Sinhgad College of Pharmacy, Vadgaon(Bk), Pune 411041, Maharashtra, India.