key: cord-0079216-y57txo9c
authors: Xiaopeng Sun; Belal, Amany; Elanany, Mohamed A.; Alsantali, Reem I.; Alrooqi, Munira M.; Mohamed, Abdalla R.; Hasabelnaby, Sherifa
title: Identification of Some Promising Heterocycles Useful in Treatment of Allergic Rhinitis: Virtual Screening, Pharmacophore Mapping, Molecular Docking, and Molecular Dynamics
date: 2022-05-26
journal: Russ J Bioorg Chem
DOI: 10.1134/s1068162022330019
sha: 2154f356812b083128d6f154499dae7b23e68aff
doc_id: 79216
cord_uid: y57txo9c

Rhinitis is an allergic disease that causes troubles and restlessness for patients. In this research work we will focus on finding promising organic molecules with potential ability to target histamine receptor with no sedative side effect. Phalazines and their isosteres, pyrimidines and pyridines have been reported to target H1 receptors, for this reason we have searched for library of these basic scaffolds, this library which has 184 organic molecules will be subjected for further explorations through computer aided drug design techniques. Swiss ADMET will be used to gather these compounds in clusters. Cluster with low potential to penetrate BBB is selected for virtual screening through pharmacophore model. Then molecular docking that revealed the stability of the complex formed between the investigated molecules and H1 receptor. ADMET profile showed three compounds (XVIII), (XX), and (XXI) with no toxicity on liver and no effect on CYP2D6, these three compounds were subjected to molecular dynamic simulations and compound (XVIII) showed the most stable complex with the target protein (H1). Finally, we can say this work helped us to find new compounds with promising potential to target H1 without ability to penetrate BBB, so they can be used as useful candidates in treatment of rhinitis and deserve to be subjected for preclinical and clinical investigations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1134/S1068162022330019.

The ADMET (absorption, distribution, metabolism, elimination and toxicity) of the cluster compounds were determined using Discovery studio 2.5 ADMET descriptor protocol

The Schrödinger Desmond package was used for the molecular dynamic simulations of our study. The structures of the complexes were imported and properly processed using "Protein Preparation" wizard using OPLS4 forcefield for energy minimization and subsequent processes [9, 12] . The systems were then built using TIP3P water molecule model in an orthorhombic periodic box with boundaries of 10 A 0 from protein atoms with salt concentration of 0.15 M NaCl. The simulations were then performed for 50 ns under the default NPT ensemble of temperature 300 K and 1 bar pressure. The analysis of the data was performed using built-in tools [13] .

The binding free energy of the examined protein-ligand complexes was calculated using the MM-GBSA approach, which combined molecular mechanics (MM) force fields with a Generalized Born and Surface Area continuum solvation solvent model. Using the default settings in Schrodinger Prime package, the OPLS4 force field, and VSGB solvent model were used for energy computations [14, 15] . Binding free energy with and with no restrain (NS) were then calculated through the following equations: dG = Ecomplex -Ereceptor -Eligand dG is the binding free energy, Ecomplex is the total energy of the complex, Ereceptor is the total energy of receptor alone and Eligand is the total energy of ligand alone. dG (NS) = dG -Restrainreceptor -Restrainligand dG (NS) is the binding free energy without consideration of , Ecomplex is the total energy of the complex, Ereceptor is the total energy of receptor alone and Eligand is the total energy of ligand alone. 

Cc1ccc2c(c1)-CC1(C[C@@](CCO1)(CCN2CC[NH+](CC2)C)c3cccc(c3)C(F)(F)F)C C20588831 P30713162 CC(C)(C)[NH+]=C1[C@H](C2(CCCCC2)C(=S)N1c3ccccc3)N4CCCC4 C15861749 P31857451 c1cc(sc1)[C@@H]2c3ccsc3CC[NH+]2Cc4coc(n4)c5ccc(cc5)F C24756601 P36649091 Cc1ccc(cc1)N(CC(=O)c2ccc(cc2)Br)C3=[NH+]CCCC3 C27526249 P40555695 Cc1ccc(cc1)[C@@H]2CC(=O)N3C[NH+](CSC3=C2C#N)C4CCCCC4CC(C)C[NH+](Cc1cc(ccc1F)C#N)C(C)C C47833917 P71607719 C[C@@H](C1CC1)[NH+](Cc2csc(n2)C(C)C)C3CC3 C47909669 P71711104 C1C[C@H]2[C@@H](C1)OCC[NH+]2CCCCCCCl C51019494 P76376718 CCC[C@H]1CCC(=O)[C@H](C1)C[NH+](C)CC(C)C C53926529 P81095861 CC(C)(C)[C@@H]1CCC(=O)[C@H](C1)C[NH+](C)CC2CC2 C53928009 P81097341 CCC[NH+](C[C@H]1C[C@@H](CCC1=O)CC)CC2CC2 C53928790 P81098122 CC[C@@H]1CCC(=O)[C@H](C1)C[NH+](CC2CC2)C(C)C C53930652 P81099992 CC(C)[C@@H]1CCC(=O)[C@@H](C1)C[NH+](C)CC(F)(F)F C54559075 P82121842 CCC1(CC[NH+](CC1)C[C@](C)(CC)C=O)CC C62956887 P96607314 CC[NH+](C[C@@H]1C[C@@H](CCC1=O)C(C)(C)C)CC2CC2 C69239785 P106456480 C1CC[C@@H](C(=O)CC1)C[NH+](CC2CC2)CC3CC3 C70507015 P108757575 C1CCO[C@H](C1)C[NH+](CCCl)C2CCCC2 C71057967 P128823522 CC[C@@H](C[NH+](CC)C[C@@H](C)C#N)CBr C83162124 P129983888 CCCc1[nH+]ccn1CC[C@H](C)CCBr C84028357 P131463052 C[C@@H]1C[C@H]([C@@H](C(=O)C1)C[NH+](CC2CC2)C(C)C)C C84940045 P132931658 CCCn1cc[nH+]c1CCC[C@@H](CC)Br C86754900 P135794938 CC(C)[C@@H](C[NH+](C)C1CCN(CC1)C)CS C87055212 P136258794 CCC(CC)(Cn1c(c(c([nH+]1)C)C)C)CS C87093749 P136321220 CCC[NH+](CCC(C)(C)C#N)CC(F)(F)F C87595459 P137021546 CCCCN(CCBr)c1c(ccc[nH+]1)C C87750223 P137250819 CCCCN(CCBr)c1[nH+]ccs1 C87750330 P137264624 C[C@@H]1CCC[C@@H](C1)CC[NH+](C)C[C@@H]2CCOC2 C89139897 P139407140 C1CCCC(CC1)(C[NH+](CC2CC2)C3CC3)C=O C89561388 P139993176 CC1CCC(CC1)(C[NH+](C)[C@H](C)C(C)C)C=O C89578589 P140024493 C[C@@H]1CCC[C@@](C1)(C[NH+](C)Cc2ccsc2)C=O C89611877 P140080690 C[C@H]1CCC[C@@](C1)(C[NH+](C)CCC(C)C)C=O C89612404 P140081330 C[C@H]1CCC[C@](C1)(C[NH+](C)C[C@@H]2C[C@@H]2C)C=O C89612673 P140081599 C[C@H]1CCC[C@@](C1)(C[NH+](C)Cc2cccs2)C=O C89611874 P140106860 C1CCC(C1)C[NH+](C[C@@H]2CCCO2)[C@@H]3CCSC3 C89952376 P140607811 c1cc2c(cc1F)C[C@H](O2)C[NH+](CCCl)C3CC3 C90895308 P142180975 CCC[C@@H](C)CC(=O)C1(CCCC1)[NH+]2CCCC2 C91639944 P143439579 CC[NH+](Cc1ccc(cc1)OCC#C)CC(F)(F)F C91813187 P143745504 Cc1ccc(s1)C[NH+](CC2=CCCOC2)C(C)C C92485325 P144773314 CC[C@H](C)[C@H](C)[NH+](Cc1c(ncs1)C)C2CC2 C93132268 P145814524 CC[C@H](C)C[NH+](CC)[C@@H]1C[C@@H](CC[C@@H]1C#N)C C93251001 P145985546 CC[C@]1(CCC[NH+](C1)CC(C)(C)CCC#N)C C93459082 P146345605 CC[C@H]1CCCCC[NH+]1CC(C)(C)CCC#N C93530273 P146467671 CCC(CC)C[NH+]1CCN(CC1)[C@@H]2C[C@H]3CC[C@@H]2C3 C93705462 P146804249 CC[C@H]1CN2CCCC[C@@H]2C[NH+]1C[C@@H](C)CSC C94434774 P148004895 CCC(CC)(C[NH+](C)CC1CCOCC1)CS C94577774 P148254426 CC(C)(C)[C@H](CN1CC[C@@H](C1)[NH+]2CCCC2)CS C94579395 P148256051 CCC[C@H](CN1CC[NH+]2CCCC[C@@H]2C1)CS C94582043 P148262003 CCC(CC)(C[NH+]1CCO[C@H]2[C@@H]1CCCC2)CS C94581224 P148263647 C[C@H](CCn1cc[nH+]c1c2cccs2)CCS C94588086 P148270556 CCN(Cc1cccc[nH+]1)c2ccc(cc2)CCl C94920726 P148787354 Cc1ccc(cc1)NC(=S)N[C@@H](C(Cl)(Cl)Cl)NC(=O)c2ccc(c(c2)OC)OC C00836932 P06692610 Cc1ccc(cc1S(=O)(=O)Nc2ccc(cc2)SC(F)F)NC(=S)NC3CCCCC3 C05941946 P09114875 Cc1ccc(cc1C)NC(=S)NNS(=O)(=O)c2cc(cc(c2)C(F)(F)F)C(F)(F)F C01037260 P09472398 Cc1ccc(c(c1)S(=O)(=O)Nc2ccc(cc2)Br)NC(=S)NCc3ccccc3 C03277853 P09587503 CCc1c(sc(c1C(=O)OC)NC(=S)NNC(=O)[C@H]2C[C@H]2c3ccc(cc3)C(C)(C)C)C C02856729 P10357878 C[C@H]1CCc2c(sc(c2C(=O)N)NC(=O)/C=C/c3ccc(c(c3)OC)OCc4ccccc4)C1 C00953827 P12884256 Cc1ccc(c(c1)NC(=S)N[C@@H](C(Cl)(Cl)Cl)NC(=O)Cc2ccc(cc2OC)OC)C C08859109 P13601346 CCCCOc1ccc(cc1Br)C(=O)NC(=S)Nc2ccc(cc2)NC(=O)CC(C)C C09259881P14186768

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