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Molecular pharmacophore selectivity studies, virtual screening, and in silico ADMET analysis of GPCR antagonists

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Abstract

The G protein-coupled receptors (GPCRs), especially amine type, comprise the largest family of proteins targeted by drug discovery. One of the major hurdles in the design of safe and effective drugs targeting GPCRs is finding ligands that are highly selective for a specific receptor subtype. To gain insights into the structural basis of ligand subtype selectivity within the family of amine receptors (D1, D2, D3, D4, Alpha1, 5HT1a, and 5HT2a), we generated 3D selective pharmacophore models of all seven subtypes. The performance of 3D molecular descriptors for rational design to maximize the structural selectivity of amine GPCR antagonists with different selectivity profile is investigated in this publication. Different family- and target-specific 3D pharmacophore models were built and applied for selectivity searching to evaluate their performance in identifying target-selective hits. Five amine antagonists of highly selectivity prediction were obtained as potential hits using virtual screening protocol of selective models in ZINC database. This study of multiple pharmacophore mapping provided deep insight for identifying subtype-selectivity determinants that can be used as novel tool for discovery of selective and potent GPCR amine antagonists which could be used for treatment of different GPCR-linked diseases.

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References

  • Ball T, Perregaard J, Ramirez MT, Larsen AK, Soby KK, Liljefors T, Andersen K (2003) Synthesis and structural–affinity relationship investigations of 5-heteroaryl-substitiuted analogues of the antipsychotic sertindole: a new class of highly selective alpha (1) adrenoceptor antagonists. J Med Chem 46:265–283

    Article  Google Scholar 

  • Bender A, Glen C (2004) Molecular similarity: a key technique in molecular informatics. Org Biomol Chem 2:3204–3218

    Article  CAS  PubMed  Google Scholar 

  • Betti L, Botta M, Corelli F, Floridi M, Giannaccini G, Maccari L, Manetti F, Strappaghetti G, Tafi A, Corsano S (2002) Alpha(1)-adrenoceptor antagonists—4: pharmacophore-based design, synthesis, and biological evaluation of new imidazo-, benzimidazo-, and indoloarylpiperazine derivatives. J Med Chem 45:3603–3611

    Article  CAS  PubMed  Google Scholar 

  • Bettinetti L, Schlotter K, Hubner H, Gmeiner P (2002) Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists. J Med Chem 45:4594–4597

    Article  CAS  PubMed  Google Scholar 

  • Bolognesi ML, Budriesi R, Chiarini A, Poggesi E, Leonardi A, Melchiorre C (1998) Design, synthesis, and biological activity of prazosin-related antagonists: role of the piperazine and furan units of prazosin on the selectivity for alpha1-adrenoreceptor subtypes. J Med Chem 41:4844–4853

    Article  CAS  PubMed  Google Scholar 

  • Byrtus H, Pawlowski M, Czopek A, Bojarski A, Duszynska B, Nowak G, Klodzinska A, Tatarczynska E, Wesolowska A, Wojcik E (2005) Synthesis and 5-HT1A, 5-HT2A receptor activity of new β-tetralonohydantoins. Eur J Med Chem 40:820–829

    Article  CAS  PubMed  Google Scholar 

  • Egle I, Barriault N, Bordeleau M, Drage J, Dube L, Peraqine J, Mazzocco L, Arora J, Jarvie K, Tehim A (2004) N-(1-Benzylpyrrolidin-3-yl)arylbenzamides as potent and selective human dopamine D4 antagonists. Bioorg Med Chem Lett 14:4847–4850

    Article  CAS  PubMed  Google Scholar 

  • Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A (2006) 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazol[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist. J Med Chem 49:3938–3947

    Article  CAS  PubMed  Google Scholar 

  • Faraci WS, Zorn SH, Sanner MA, Fliri A (1998) The discovery of potent and selective dopamine D4 receptor antagonists. Curr Opin Chem Biol 2:535–540

    Article  CAS  PubMed  Google Scholar 

  • Fiorino F, Perissutti E, Serverino B, Santagada V, Cirillo D, Terracciano S, Massarelli P, Bruni G, Collavoli E, Renner C, Caliendo G (2005) New 5-hydroxytryptamine 1A receptor ligands containing a norbornene nucleus: synthesis and in vitro pharmacological evaluation. J Med Chem 48:5495–5503

    Article  CAS  PubMed  Google Scholar 

  • Geneste H, Amberg W, Backfisch G, Beyerbach A, Braje W, Delzer J, Haupt A, Hutchins C, King L, Sauer D, Unger L, Wernet W (2006a) Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme. Bioorg Med Chem Lett 16:1934–1937

    Article  CAS  PubMed  Google Scholar 

  • Geneste H, Backfisch G, Braje W, Delzer J, Haupt A, Hutchins C, King L, Lubisch W, Steiner G, Teschendorf H, Unger L, Wernet W (2006b) Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: quinolin(di)one and benzazepin(di)one derivatives. Bioorg Med Chem Lett 16:658–662

    Article  CAS  PubMed  Google Scholar 

  • Graff CD, Rognan D (2009) Customizing G protein-coupled receptor models for structure-based virtual screening. 35:4026–4048. http://www.ncbi.nlm.nih.gov/pubmed/20028320

  • Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH (2005) Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor. J Med Chem 48(3):839–848

    Article  CAS  PubMed  Google Scholar 

  • Heinrich T, Bottcher H, Prucher H, Gottsclich R, Ackermann K, Amsterdam C (2006) 1-(1-Phenethylpiperidin-4-yl)-1-phenylethanols as Potent and Highly Selective 5-HT2A Antagonists. ChemMedChem 1:245–255

    Article  CAS  PubMed  Google Scholar 

  • Hodgetts KJ, Kieltyka A, Brodbeck R, Tran JN, Wasley WF, Thurkauf A (2001) 6-(4-Benzylpiperazin-1-yl)benzodioxanes as selective ligands at cloned primate dopamine D(4) receptors. Bioorg Med Chem 9:3207–3213

    Article  CAS  PubMed  Google Scholar 

  • Irwin J, Shoichet B (2005) ZINC: a free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klabunde T, Evers A (2005) GPCR antitarget modelling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects. ChemBioChem 6:876–889

    Article  CAS  PubMed  Google Scholar 

  • Klabunde T, Hessler G (2002) Drug design strategies for targeting G-protein-coupled receptors. ChemBioChem 3:928–944

    Article  CAS  PubMed  Google Scholar 

  • Kulagowski J, Broughton H, Curtis N, Mawer I, Ridgill M, Baker R, Emms F, Freedmann S, Marwood R, Patel S, Patel S, Ragan C, Leeson P (1996) 3-[[4-(4-Chlorophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem 39:1941–1942

    Article  CAS  PubMed  Google Scholar 

  • MACCS (2005) Structural keys; Symyx Software. San Ramon, CA

  • Macdonald GJ, Branch CL, Hadley MS, Johnson CN, Nash DJ, Smith AB, Stemp G, Thewlis KM, Vong AK, Austin NE, Jeffrey P, Winborn KY, Boyfield I, Hagan JJ, Middlemiss DN, Reavill C, Riley GJ, Watson JM, Wood M, Parker SG, Ashby CR Jr (2003) Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796): a potent and selective dopamine D3 receptor antagonist. J Med Chem 46:4952–4964

    Article  CAS  PubMed  Google Scholar 

  • Maryanoff B, McComsey D, Martin G, Shank R (1998) Azepinoindole derivatives with high affinity for brain dopamine and serotonin receptors. Bioorg Med Chem Lett 8:983–988

    Article  CAS  PubMed  Google Scholar 

  • Mason S, Good C, Martin J (2001) 3-D pharmacophores in drug discovery. Curr Pharm Des 7:567–597

    Article  CAS  PubMed  Google Scholar 

  • Molecular Drug Data Report (MDDR), Elsevier MDL, San Leandro, CA. http://www.mdl.com

  • Molecular Operating Environment (MOE) (2012) Chemical Computing Group, Montreal. http://www.chemcomp.com

  • Moll A, Hubner H, Gmeiner P, Troschutz R (2002) Phenylpiperazinylmethylindolecarboxylates and derivatives as selective D(4)-ligands. Bioorg Med Chem 10:1671–1679

    Article  CAS  PubMed  Google Scholar 

  • Obniska J, Kołaczkowski M, Charakchieva-Minol S, Nedza K, Dybała M, Bojarski AJ (2005) Synthesis, anticonvulsant properties and 5-HT1A/5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]–2–aza-spiro[4.4]nonane and [4.5]decane-1,3-dione derivatives. Pharmacol Rep 57:336–344

    CAS  PubMed  Google Scholar 

  • OSIRIS (2012) Property explorer. http://www.organic-chemistry.org/prog/peo

  • Patane E, Pittala V, Guerrera F, Salerno L, Romeo G, Siracusa MA, Russo F, Manetti F, Botta M, Mereghetti I, Cagnotto A, Mennini T (2005) Synthesis of 3-arylpiperazinylalkylpyrrolo [3, 2-d]pyrimidine-2,4-dione derivatives as novel, potent, and selective alpha1-adrenoceptor ligands. J Med Chem 48:2420–2431

    Article  CAS  PubMed  Google Scholar 

  • Peglion J, Goument B, Despaux N, Charlot V, Giraud H, Nisole C, Newman-Tancredi AN, Dekeyne A, Bertrand M, Genissel P, Millan M (2002) Improvement in the selectivity and metabolic stability of the serotonin 5-HT(1A) ligand, S 15535: a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols. J Med Chem 45:165–176

    Article  CAS  PubMed  Google Scholar 

  • Perrone R, Berardi F, Colabufo NA, Leopoldo M, Tortorella V (2000) 1-Substituted-4-[3-(1,2,3,4-tetrahydro-5- or 7-methoxynaphthalen-1-yl)propyl]piperazines: influence of the N-1 piperazine substituent on 5-HT(1A) receptor affinity and selectivity versus D2 and alpha1 receptors—Part 6. Bioorg Med Chem 8:873–881

    Article  CAS  PubMed  Google Scholar 

  • Perrone R, Berardi F, Colabufo NA, Leopoldo M, Lacivita E, Tortorella V, Leonardi A, Pogessi E, Testa R (2001) trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: a new class of potent and selective 5-HT(1A) receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphtalen-1-yl)propyl]-1-arylpiperazines. J Med Chem 44:4431–4442

    Article  CAS  PubMed  Google Scholar 

  • Reitz A, Baxter E, Codd E, Davis C, Jordan A, Maryanoff B, Maryanoff C, McDonnell M, Powell E, Renzi M, Schott M, Scott M, Shank R, Vaught J (1998) Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic α1 receptors. J Med Chem 41:1997–2009

    Article  CAS  PubMed  Google Scholar 

  • Sasikumar TK, Burnett DA, Zhang H, Smith-Torhan A, Fawzi A, Lachowicz JE (2006) Hydrazides of clozapine: a new class of D1 dopamine receptor subtype selective antagonists. Bioorg Med Chem Lett 16:4543–4547

    Article  CAS  PubMed  Google Scholar 

  • Schwartz TW, Rosenkilde MM (1996) Dogmas versus data in 7TM ‘locks’ for ‘keys’. Trends Pharmacol Sci 17:213–216

    Article  CAS  PubMed  Google Scholar 

  • Stumpfe D, Ahmed HE, Vogt I, Bajorath J (2007) Methods for computer-aided chemical biology—part 1: design of a benchmark system for the evaluation of compound selectivity. Chem Biol Drug Des 70:182–194

    Article  CAS  PubMed  Google Scholar 

  • Su J, Tang H, McKittrick BA, Burnett DA, Zhang H, Smith-Torhan A, Fawzi A, Lachowicz J (2006) Modification of the clozapine structure by parallel synthesis. Bioorg Med Chem Lett 16:4548–4553

    Article  CAS  PubMed  Google Scholar 

  • Sukalovic V, Andric D, Roglic G, Kostic-Rajacic S, Schrattenholz A, Soskic V (2005) Synthesis, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazine-1-yl)propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs. Eur J Med Chem 40:481–493

    Article  CAS  PubMed  Google Scholar 

  • Trumpp-Kallmeyer S, Hoflack J, Bruinvels A, Hibert M (1992) Modeling of G-protein-coupled receptors: application to dopamine, adrenaline, serotonin, acetylcholine, and mammalian opsin receptors. J Med Chem 35:3448–3462

    Article  CAS  PubMed  Google Scholar 

  • Vangveravong S, McElveen E, Taylor M, Xu J, Tu Z, Luedtke RR, Mach RH (2006) Synthesis and characterization of selective dopamine D2 receptor antagonists. Bioorg Med Chem 14:815–825

    Article  CAS  PubMed  Google Scholar 

  • Vogt I, Stumpfe D, Ahmed HEA, Bajorath J (2007) Methods for computer-aided chemical biology—part 2: evaluation of compound selectivity using 2D molecular fingerprints. Chem Biol Drug Des 70:195–205

    Article  CAS  PubMed  Google Scholar 

  • Vogt I, Ahmed HE, Auer J, Bajorath J (2008) Exploring structure-selectivity relationships of biogenic amine GPCR antagonists using similarity searching and dynamic compound mapping. Mol Divers 12:25–40

    Article  CAS  PubMed  Google Scholar 

  • Willett P (2005) Searching techniques for databases of two and three-dimensional structures. J Med Chem 48:4183–4199

    Article  CAS  PubMed  Google Scholar 

  • Zhang A, Neumeyer JL, Baldessarini RJ (2007a) Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chem Rev 107:274–302

    Article  CAS  PubMed  Google Scholar 

  • Zhang A, Zhang Y, Branfman AR, Baldessarini RJ, Neumeyer JL (2007b) Advances in development of dopaminergic aporphinoids. J Med Chem 50:171–181

    Article  CAS  PubMed  Google Scholar 

  • Zhao H, He X, Thurkauf A, Hoffman D, Kieltyka A, Brodbeck R, Primus R, Wasley JW (2002a) Indoline and piperazine containing derivatives as a novel class of mixed D(2)/D(4) receptor antagonists—part 2: asymmetric synthesis and biological evaluation. Bioorg Med Chem Lett 12:3111–3115

    Article  CAS  PubMed  Google Scholar 

  • Zhao H, Thurkauf A, He X, Hodgetts K, Zhang X, Rachwal S, Kover R, Hutchison A, Peterson J, Kieltyka A, Brodbeck R, Primus R, Wasley JW (2002b) Indoline and piperazine containing derivatives as a novel class of mixed D(2)/D(4) receptor antagonists—part 1: identification and structure–activity relationships. Bioorg Med Chem Lett 12:3105–3109

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge support from the Deanship of Scientific Research at Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia (Project Nr. 4318/1434).

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Authors and Affiliations

  1. Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia

    Hany Emary Ali Ahmed, Mohamed F. Zayed & Saleh Ihmaid

  2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Hany Emary Ali Ahmed

  3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Mohamed F. Zayed

  4. School of Pharmacy and Applied Science, La Trobe University, Bendigo, Australia

    Saleh Ihmaid

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  1. Hany Emary Ali Ahmed
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  2. Mohamed F. Zayed
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Correspondence to Hany Emary Ali Ahmed.

Appendix

Appendix

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Table 7 Detailed composition and literature sources of the selectivity sets
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Ahmed, H.E.A., Zayed, M.F. & Ihmaid, S. Molecular pharmacophore selectivity studies, virtual screening, and in silico ADMET analysis of GPCR antagonists. Med Chem Res 24, 3537–3550 (2015). https://doi.org/10.1007/s00044-015-1389-6

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