Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

References

• Wang R, Burnett AL, Heller WH, et al. Selectivity of Avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability. J Sex Med 2012;9:2122–9.
   PubMed Web of Science ®Google Scholar
• Corbin JD, Francis SH, Webb DJ. Phosphodiesterase Type 5 as a pharmacologic target in erectile dysfunction. Urology 2002;60:4–11.
   PubMed Web of Science ®Google Scholar
• Rotella D. Phosphodiesterase 5 Inhibitors: Current Status and Potential Applications. Nat Rev Drug Discov 2002;1:674–82.
   PubMed Web of Science ®Google Scholar
• Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93:280–91.
   PubMed Web of Science ®Google Scholar
• Terrett NK, Bell AS, Brown D, Ellis P. Sildenafil (Viagra(TM)), a potent and selective inhibitor of Type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 1996;6:1819–24.
   Web of Science ®Google Scholar
• Srivani P, Srinivas E, Raghu R, Sastry GN. Molecular modeling studies of pyridopurinone derivatives-potential phosphodiesterase 5 inhibitors. J Mol Graph Model 2007;26:378–90.
   PubMed Web of Science ®Google Scholar
• Sakamoto T, Koga Y, Hikota M, et al. 8-(3-Chloro-4-Methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors. Bioorg Med Chem Lett 2015;25:1431–5.
   PubMed Web of Science ®Google Scholar
• Sakamoto T, Koga Y, Hikota M, et al. The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor. Bioorg Med Chem Lett 2014;24:5460–5.
   PubMed Web of Science ®Google Scholar
• Sakamoto T, Koga Y, Hikota M, et al. Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation. Bioorg Med Chem Lett 2014;24:5175–80.
   PubMed Web of Science ®Google Scholar
• Wang Z, Zhu D, Yang X, et al. The selectivity and potency of the new PDE5 inhibitor TPN729MA. J Sex Med 2013;10:2790–7.
   PubMed Web of Science ®Google Scholar
• Duan H, Zheng J, Lai Q, et al. 2-Phenylquinazolin-4(3H)-One, a class of potent PDE5 inhibitors with high selectivity versus PDE6. Bioorg Med Chem Lett 2009;19:2777–9.
   PubMed Web of Science ®Google Scholar
• Choi H, Lee J, Kim YH, et al. Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533). Bioorg Med Chem Lett 2010;20:383–6.
   PubMed Web of Science ®Google Scholar
• Owen DR, Walker JK, Jon Jacobsen E, et al. Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2009;19:4088–91.
   PubMed Web of Science ®Google Scholar
• Kim YH, Choi H, Lee J, et al. Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction. Bioorg Med Chem Lett 2008;18:6279–82.
   PubMed Web of Science ®Google Scholar
• Arnold NJ, Arnold R, Beer D, et al. Potent and selective xanthine-based inhibitors of phosphodiesterase 5. Bioorg Med Chem Lett 2007;17:2376–9.
   PubMed Web of Science ®Google Scholar
• Giovannoni MP, Vergelli C, Biancalani C, et al. Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction. J Med Chem 2006;49:5363–71.
   PubMed Web of Science ®Google Scholar
• Yang GF, Lu HT, Xiong Y, Zhan CG. Understanding the structure–activity and structure–selectivity correlation of cyclic guanine derivatives as phosphodiesterase-5 inhibitors by molecular docking, CoMFA and CoMSIA analyses. Bioorg Med Chem 2006;14:1462–73.
   PubMed Web of Science ®Google Scholar
• Xia G, Li J, Peng A, et al. Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives. Bioorg Med Chem Lett 2005;15:2790–4.
   PubMed Web of Science ®Google Scholar
• Jiang W, Alford VC, Qiu Y, et al. Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors. Bioorg Med Chem 2004;12:1505–15.
   PubMed Web of Science ®Google Scholar
• Pissarnitski DA, Asberom T, Boyle CD, et al. SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunction. Bioorg Med Chem Lett 2004;14:1291–4.
   PubMed Web of Science ®Google Scholar
• Daugan A, Grondin P, Ruault C, et al. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem 2003;46:4533–42.
   PubMed Web of Science ®Google Scholar
• Ukita T, Nakamura Y, Kubo A, et al. 1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors. Bioorg Med Chem Lett 2003;13:2341–5.
   PubMed Web of Science ®Google Scholar
• Maw GN, Allerton CM, Gbekor E, Million WA. Design, synthesis and biological activity of beta-carboline-based type-5 phosphodiesterase inhibitors. Bioorg Med Chem Lett 2003;13:1425–8.
   PubMed Web of Science ®Google Scholar
• Jiang W, Sui Z, Macielag MJ, et al. Furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors for treatment of erectile dysfunction. J Med Chem 2003;46:441–4.
   PubMed Web of Science ®Google Scholar
• Wang Y, Chackalamannil S, Hu Z, et al. Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2002;12:3149–52.
   PubMed Web of Science ®Google Scholar
• Bi Y, Stoy P, Adam L, et al. The discovery of novel, potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2001;11:2461–4.
   PubMed Web of Science ®Google Scholar
• Wang G, Liu Z, Chen T, et al. Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5. J Med Chem 2012;55:10540–50.
   PubMed Web of Science ®Google Scholar
• Bi Y, Stoy P, Adam L, et al. Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction. Bioorg Med Chem Lett 2004;14:1577–80.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Artemyev NO. Determinants for phosphodiesterase 6 inhibition by its gamma-subunit. Biochemistry 2010;49:3862–7.
   PubMed Web of Science ®Google Scholar
• Barren B, Gakhar L, Muradov H, et al. Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit. EMBO J 2009;28:3613–22.
   PubMed Web of Science ®Google Scholar
• Liu YT, Matte SL, Corbin JD, et al. Probing the catalytic sites and activation mechanism of photoreceptor phosphodiesterase using radiolabeled phosphodiesterase inhibitors. J Biol Chem 2009;284:31541–7.
   PubMed Web of Science ®Google Scholar
• Zhang X, Feng Q, Cote RH. Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Investig Ophthalmol Vis Sci 2005;46:3060–6.
   PubMed Web of Science ®Google Scholar
• Granovsky AE, Artemyev NOA. Conformational switch in the inhibitory γ-subunit of PDE6 upon enzyme activation by transducin. Biochemistry 2001;40:13209–15.
   PubMed Web of Science ®Google Scholar
• Cahill KB, Quade JH, Carleton KL, Cote RH. Identification of amino acid residues responsible for the selectivity of tadalafil binding to two closely related phosphodiesterases, PDE5 and PDE6. J Biol Chem 2012;287:41406–16.
   PubMed Web of Science ®Google Scholar
• Pissarnitski D. Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: attaining selectivity versus PDE6. Med Res Rev 2006;26:369–95.
   PubMed Web of Science ®Google Scholar
• Kerr NM, Danesh-Meyer HV. Phosphodiesterase inhibitors and the eye. Clin Exp Ophthalmol 2009;37:514–23.
   PubMed Web of Science ®Google Scholar
• Foresta C, Caretta N, Zuccarello D, et al. Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects. Eye (Lond) 2008;22:144–9.
   PubMed Web of Science ®Google Scholar
• Makhlouf A, Kshirsagar A, Niederberger C. Phosphodiesterase 11: a brief review of structure, expression and function. Int J Impot Res 2006;18:501–9.
   PubMed Web of Science ®Google Scholar
• Bischoff E. Potency, selectivity, and consequences of nonselectivity of PDE inhibition. Int J Impot Res 2004;16:S11–S14.
   PubMed Web of Science ®Google Scholar
• Ukita T, Nakamura Y, Kubo A, et al. Novel, potent, and selective phosphodiesterase 5 inhibitors: synthesis and biological activities of a series of 4-aryl-1-isoquinolinone derivatives. J Med Chem 2001;44:2204–18.
   PubMed Web of Science ®Google Scholar
• Mohamed HA, Girgis NMR, Wilcken R, et al. Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties. J Med Chem 2011;54:495–509.
   PubMed Web of Science ®Google Scholar
• Bunnage ME, Mathias JP, Wood A, et al. Highly potent and selective chiral inhibitors of PDE5: an illustration of Pfeiffer's rule. Bioorg Med Chem Lett 2008;18:6033–6.
   PubMed Web of Science ®Google Scholar
• Simon A, Barabas P, Kardos J. Structural determinants of phosphodiesterase 6 response on binding catalytic site inhibitors. Neurochem Int 2006;49:215–22.
   PubMed Web of Science ®Google Scholar
• Chen G, Wang H, Robinson H, et al. An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies. Biochem Pharmacol 2008;75:1717–28.
   PubMed Web of Science ®Google Scholar
• Cichero E, D’Ursi P, Moscatelli M, et al. Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors. Chem Biol Drug Des 2013;82:718–31.
   PubMed Web of Science ®Google Scholar
• Xiong Y, Lu H, Zhan C. Dynamic structures of phosphodiesterase-5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations. J Comput Chem 2008;29:1259–67.
   PubMed Web of Science ®Google Scholar
• Huang YY, Li Z, Cai YH, et al. The molecular basis for the selectivity of tadalafil toward phosphodiesterase 5 and 6: a modeling study. J Chem Inf Model 2013;53:3044–53.
   PubMed Web of Science ®Google Scholar
• Mittal A, Paliwal S, Sharma M, et al. Pharmacophore based virtual screening, molecular docking and biological evaluation to identify novel PDE5 inhibitors with vasodilatory activity. Bioorg Med Chem Lett 2014;24:3137–41.
   PubMed Web of Science ®Google Scholar
• Li Y, Wu W, Ren H, et al. Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: an in silico analysis. J Mol Graph Model 2012;38:112–22.
   PubMed Web of Science ®Google Scholar
• Tömöri T, Hajdú I, Barna L, et al. Combining 2D and 3D in silico methods for rapid selection of potential PDE5 inhibitors from multimillion compounds’ repositories: biological evaluation. Mol Divers 2012;16:59–72.
   PubMed Web of Science ®Google Scholar
• Antunes JE, Freitas MP, da Cunha EFF, et al. In silico prediction of novel phosphodiesterase type-5 inhibitors derived from sildenafil, vardenafil and tadalafil. Bioorg Med Chem 2008;16:7599–606.
   PubMed Web of Science ®Google Scholar
• Yoo J, Thai KM, Kim DK, et al. 3D-QSAR studies on sildenafil analogues, selective phosphodiesterase 5 inhibitors. Bioorg Med Chem Lett 2007;17:4271–4.
   PubMed Web of Science ®Google Scholar
• Zagrovic B, Van Gunsteren WF. Computational analysis of the mechanism and thermodynamics of inhibition of phosphodiesterase 5A by synthetic ligands. J Chem Theory Comput 2007;3:301–11.
   PubMed Web of Science ®Google Scholar
• Weeks JL, II, Corbin JD, Francis SH. Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. J Pharmacol Exp Ther 2009;331:133–41.
   PubMed Web of Science ®Google Scholar
• Wang H, Liu Y, Huai Q, et al. Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem 2006;281:21469–79.
   PubMed Web of Science ®Google Scholar
• Molecular Operating Environment (MOE), 2013.08. Canada: Chemical Computing Group Inc.; 2015.
   Google Scholar
• Irwin JJ, Sterling T, Mysinger MM, et al. ZINC: a free tool to discover chemistry for biology. J Chem Inf Model 2012;52:1757–68.
   PubMed Web of Science ®Google Scholar
• Sheridan RP, Kearsley SK. Why do we need so many chemical similarity search methods? Drug Discov Today 2002;7:903–11.
   PubMed Web of Science ®Google Scholar
• Willett P. Similarity-based virtual screening using 2D fingerprints. Drug Discov Today 2006;11:1046–53.
   PubMed Web of Science ®Google Scholar
• Jones G, Willett P, Glen RC, et al. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997;267:727–48.
   PubMed Web of Science ®Google Scholar
• Berendsen HJC, Spoel van der D, Drunen van R. GROMACS: a message-passing parallel molecular dynamics implementation. Comp Phys Commun 1995;91:43–56.
   Web of Science ®Google Scholar
• Schüttelkopf AW, van Aalten DM. PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr D Biol Crystallogr 2004;60:1355–63.
   PubMed Web of Science ®Google Scholar
• Frisch MJ, Trucks GW, Schlegel HB, et al. Wallingford, CT: Gaussian Inc.; 2009.
   Google Scholar
• Rastelli G, Rio del A, Degliesposti G, Sgobba M. Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA. J Comput Chem 2010;31:797–810.
   PubMed Web of Science ®Google Scholar
• Card GL, England BP, Suzuki Y, et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 2004;12:2233–47.
   PubMed Web of Science ®Google Scholar
• Zhang KYJ, Card GL, Suzuki Y, et al. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell 2004;15:279–86.
   PubMed Web of Science ®Google Scholar
• Sung B, Hwang K, Jeon Y, et al. Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 2003;425:98–102.
   PubMed Web of Science ®Google Scholar
• Wang H, Ye M, Robinson H, et al. Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol 2008;73:104–10.
   PubMed Web of Science ®Google Scholar
• The UniProt Consortium. UniProt: a hub for protein information. Nucleic Acids Res 2015;43:D204–12.
   PubMed Web of Science ®Google Scholar
• Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera – a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605–12.
   PubMed Web of Science ®Google Scholar
• El-Gamil DS, Ahmed NS, Gary BD, et al. Design of novel β-carboline derivatives with pendant 5-bromothienyl and their evaluation as phosphodiesterase-5 inhibitors. Arch Pharm (Weinheim) 2013;346:23–33.
   PubMed Web of Science ®Google Scholar
• Witchel HJ. Drug-induced hERG block and long QT syndrome. Cardiovasc Ther 2011;29:251–9.
   PubMed Web of Science ®Google Scholar
• Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006;440:463–9.
   PubMed Web of Science ®Google Scholar
• Dustan Sarazan R, Crumb WJ, Beasley CM, et al. Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5 – sildenafil, tadalafil, and vardenafil. Eur J Pharmacol 2004;502:163–7.
   PubMed Web of Science ®Google Scholar
• Lees-Miller JP, Subbotina JO, Guo J, et al. Interactions of H562 in the S5 helix with T618 and S621 in the pore helix are important determinants of hERG1 potassium channel structure and function. Biophys J 2009;J96:3600–10.
   Web of Science ®Google Scholar
• Durdagi S, Subbotina J, Lees-Miller J, et al. Insights into the molecular mechanism of hERG1 channel activation and blockade by drugs. Curr Med Chem 2010;17:3514–32.
   PubMed Web of Science ®Google Scholar
• Subbotina J, Yarov-Yarovoy V, Lees-Miller J, et al. Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations. Proteins 2010;78:2922–34.
   PubMed Web of Science ®Google Scholar
• Durdagi S, Duff HJ, Noskov SY. Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain. J Chem Inf Model 2011;51:463–74.
   PubMed Web of Science ®Google Scholar
• Durdagi S, Deshpande S, Duff HJ, Noskov SY. Modeling of open, closed, and open-inactivated states of the hERG1 channel: structural mechanisms of the state-dependent drug binding. J Chem Inf Model 2012;52:2760–74.
   PubMed Web of Science ®Google Scholar
• Guo J, Durdagi S, Changalov M, et al. Structure driven design of novel human ether-a-go-go-related-gene channel (hERG1) activators. PLoS One 2014;9:e105553.
   PubMed Web of Science ®Google Scholar
• Durdagi S, Randall T, Duff HJ, et al. Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity. BMC Pharmacol Toxicol 2014;15:14.
   PubMed Web of Science ®Google Scholar
• Guo J, Cheng YM, Lees-Miller JP, et al. NS1643 interacts around L529 of hERG to alter voltage sensor movement on the path to activation. Biophys J 2015;108:1400–13.
   PubMed Web of Science ®Google Scholar
• Durdagi S, Guo J, Lees-Miller J, et al. Structure-guided topographic mapping and mutagenesis to elucidate binding sites for the Herg1 potassium channel (KCNH2) activator-NS1643. J Pharmacol Exp Ther 2012;342:441–52.
   PubMed Web of Science ®Google Scholar
• Anwar-Mohamed A, Barakat KH, Bhat R, et al. A human ether-a-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity. Toxicol Lett 2014;230:382–92.
   PubMed Web of Science ®Google Scholar
• Dempsey CE, Wright D, Colenso CK, et al. Assessing hERG pore models as templates for drug docking using published experimental constraints: the inactivated state in the context of drug block. J Chem Inf Model 2014;54:601–12.
   PubMed Web of Science ®Google Scholar
• Sastry GM, Adzhigirey Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 2013;27:221–34.
   PubMed Web of Science ®Google Scholar