Renin inhibitors pertain to a new generation class of antihypertensive agents. There are only a few studies on the computational modeling of such class of compounds and only one available drug in the market used as renin inhibitor for the treatment of hypertension, aliskiren. The present study reports the QSAR modeling of the activities of a series of indole-3-carboxamide derivatives using MIA-QSAR in order to propose new promising analogs as renin inhibitor candidates. The proposed structures were submitted to docking evaluation to search for the interaction modes responsible for the calculated bioactivities. In addition, the drug likeness of the proposed compounds was investigated using theoretical data related to pharmacokinetic properties. Overall, at least two promising candidates are proposed as highly active and pharmacokinetically acceptable renin inhibitors.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
ACD/ChemSketch Version 10.02 (2006) Advanced Chemistry Development, Inc., Toronto
Cormanich RA, Freitas MP, Rittner R (2011) 2D chemical drawings correlate to bioactivities: MIA-QSAR modelling of antimalarial activities of 2,5-diaminobenzophenone derivatives. J Braz Chem Soc 22:637–642
Corminboeuf O, Bezencon O, Grisostomi C, Remen L, Richard-Bildstein S, Bur D, Prade L, Hess P, Strickner P, Fischli W, Steiner B, Treiber A (2010) Design and optimization of new piperidines as renin inhibitors. Bioorg Med Chem Lett 20:6286–6290
da Cunha EFF, Resende JE, França TCC, Gonçalves MA, Souza FR, Santos-Garcia L, Ramalho TC (2013) Molecular modeling studies of piperidine derivatives as new acetylcholinesterase inhibitors against neurodegenerative diseases. J Chem. doi:10.1155/2013/278742
da Mota EG, Silva DG, Guimarães MC, da Cunha EFF, Freitas MP (2014) Computer-assisted design of novel 1,4-dihydropyridine calcium channel blockers. Mol Simul 40:959–965
Deeb O, da Cunha EFF, Cormanich RA, Ramalho TC, Freitas MP (2012) Computer-assisted assessment of potentially useful non-peptide HIV-1 protease inhibitors. Chemometr Intell Lab Syst 116:123–127
Freitas MP (2007) Multivariate QSAR: from classical descriptors to new perspectives. Curr Comput Aided Drug Des 3:235–239
Golbraikh A, Tropsha A (2002) Beware of q 2! J Mol Graph Model 20:269–276
Guimarães MC, Silva DG, da Mota EG, da Cunha EFF, Freitas MP (2014) Computer-assisted design of dual-target anti-HIV-1 compounds. Med Chem Res 23:1548–1558
Jing T, Feng J, Zuo Y, Ran B, Liu J, He G (2012) Exploring the substructural space of indole-3-carboxamide derivatives binding to renin: a novel active-site spatial partitioning approach. J Mol Model 18:4417–4426
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25
Matlab 7.5 (2007) Mathworks Inc., Natick
Mitra I, Saha A, Roy K (2010) Exploring quantitative structure-activity relationship studies of antioxidant phenolic compounds obtained from traditional Chinese medicinal plants. Mol Simul 36:1067–1079
Nunes CA, Freitas MP (2013) Introducing new dimensions in MIA-QSAR: a case for chemokine receptor inhibitors. Eur J Med Chem 62:297–300
Nunes CA, Freitas MP, Pinheiro ACM, Bastos SC (2012) Chemoface: a novel free user-friendly interface for chemometrics. J Braz Chem Soc 23:2003–2010
Ojha PK, Mitra I, Das RN, Roy K (2011) Further exploring r 2m metrics for validation of QSPR models. Chemometr Intell Lab Syst 107:194–205
Paul M, Poyan MA, Kreutz R (2006) Physiology of local renin–angiotensin systems. Physiol Rev 86:747–803
Ramalho TC, França TCC, Rennó MN, Guimarães AP, da Cunha EFF, Kuca K (2010) Development of new acetylcholinesterase reactivators: molecular modeling versus in vitro data. Chem Biol Interact 187:436–440
Roy K, Mitra I, Kar S, Ojha PK, Das RN, Kabir H (2006) Comparative studies on some metrics for external validation of QSPR models. J Chem Inf Model 52:396–408
Roy PP, Paul S, Mitra I, Roy K (2009) On two novel parameters for validation of predictive QSAR models. Molecules 14:1660–1701
Scheiper B, Matter H, Steinhagen H, Stilz U, Böcskei Z, Fleury V, McCort G (2010) Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors. Bioorg Med Chem Lett 20:6268–6272
Silva DG, Freitas MP, da Cunha EFF, Ramalho TC, Nunes CA (2012) Rational design of small modified peptides as ACE inhibitors. Med Chem Commun 3:1290–1293
Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315–3321
Tzoupis H, Leonis G, Megariotis G, Supuran CT, Mavromoustakos T, Papadopoulos MG (2012) Dual inhibitors for aspartic proteases HIV-1 PR and renin: advancements in AIDS-hypertension-diabetes linkage via molecular docking, inhibition assays, and binding free energy calculations. J Med Chem 55:5784–5796
Wood JM, Stanton JL, Hofbauer KG (1987) Inhibitors of renin as potential therapeutic agents. J Enzyme Inhib Med Chem 1:169–185
Authors are thankful to FAPEMIG for the financial support of this research, as well as to CAPES for the studentship (E.G.M.) and to CNPq for fellowships (to E.F.F.C. and M.P.F.).
Conflict of interest
The authors declare no conflict of interest.
About this article
Cite this article
da Mota, E.G., Duarte, M.H., da Cunha, E.F.F. et al. Theoretical design of new indole-3-carboxamide derivatives as renin inhibitors. Med Chem Res 24, 3097–3106 (2015). https://doi.org/10.1007/s00044-015-1362-4