Skip to main content
SpringerLink
Log in

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various proposed mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations of thioridazine with zwitterionic and negatively charged model lipid membranes. Thioridazine partitions into the interfacial region of membranes and modifies their structural and dynamic properties, however dissimilarly so at the highest membrane-occurring concentration, that appears to be obtainable only for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug–membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Schreier S, Malheiros SV, de Paula E (2000) Surface active drugs: self-association and interaction with membranes and surfactants. Physicochemical and biological aspects. Biochim Biophys Acta 1508(1–2):210–234

    Article  CAS  Google Scholar 

  2. Imming P, Sinning C, Meyer A (2006) Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 5(10):821–834

    Article  CAS  Google Scholar 

  3. Hendrich AB, Michalak K (2003) Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr Drug Targets 4(1):23–30

    Article  CAS  Google Scholar 

  4. Khandelia H, Ipsen JH, Mouritsen OG (2008) The impact of peptides on lipid membranes. Biochim Biophys Acta Biomembr 1778(7–8):1528–1536

    Article  CAS  Google Scholar 

  5. Jutila A, Söderlund T, Pakkanen AL, Huttunen M, Kinnunen PKJ (2001) Comparison of the effects of clozapine, chlorpromazine, and haloperidol on membrane lateral heterogeneity. Chem Phys Lipids 112(2):151–163

    Article  CAS  Google Scholar 

  6. Killian JA (1998) Hydrophobic mismatch between proteins and lipids in membranes. Biochim Biophys Acta Rev Biomembr 1376(3):401–415

    Article  CAS  Google Scholar 

  7. Jensen MØ, Mouritsen OG (2004) Lipids do influence protein function—the hydrophobic matching hypothesis revisited. Biochim Biophys Acta Biomembr 1666(1–2):205–226

    Article  CAS  Google Scholar 

  8. Cantor RS (1997) The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry 36(9):2339–2344

    Article  CAS  Google Scholar 

  9. Cantor RS (1997) Lateral pressures in cell membranes: a mechanism for modulation of protein function. J Phys Chem B 101(10):1723–1725

    Article  CAS  Google Scholar 

  10. Kopec W, Telenius J, Khandelia H (2013) Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes. FEBS J. doi:10.1111/febs.12286

    Google Scholar 

  11. Seeger HM, Gudmundsson ML, Heimburg T (2007) How anesthetics, neurotransmitters, and antibiotics influence the relaxation processes in lipid membranes. J Phys Chem B 111(49):13858–13866

    Article  CAS  Google Scholar 

  12. Scheidt HA, Huster D (2008) The interaction of small molecules with phospholipid membranes studied by 1H NOESY NMR under magic-angle spinning. Acta Pharmacol Sin 29(1):35–49

    Article  CAS  Google Scholar 

  13. Barry J, Fritz M, Brender JR, Smith PES, Lee D-K, Ramamoorthy A (2009) Determining the effects of lipophilic drugs on membrane structure by solid-state NMR spectroscopy: the case of the antioxidant curcumin. J Am Chem Soc 131(12):4490–4498. doi:10.1021/ja809217u

    Article  CAS  Google Scholar 

  14. Klitgaard JK, Skov MN, Kallipolitis BH, Kolmos HJ (2008) Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. J Antimicrob Chemother 62(6):1215–1221

    Article  CAS  Google Scholar 

  15. Thanacoody HK (2007) Thioridazine: resurrection as an antimicrobial agent? Br J Clin Pharmacol 64(5):566–574. doi:10.1111/j.1365-2125.2007.03021.x

    Article  CAS  Google Scholar 

  16. Abbate E, Vescovo M, Natiello M, Cufre M, Garcia A, Gonzalez Montaner P, Ambroggi M, Ritacco V, van Soolingen D (2012) Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 67(2):473–477. doi:10.1093/jac/dkr500

    Article  CAS  Google Scholar 

  17. Lialiaris T, Pantazaki A, Sivridis E, Mourelatos D (1992) Chlorpromazine-induced damage on nucleic acids: a combined cytogenetic and biochemical study. Mutat Res Fundam Mol Mech Mutagen 265(2):155–163

    Article  CAS  Google Scholar 

  18. Sharma S, Singh A (2011) Phenothiazines as anti-tubercular agents: mechanistic insights and clinical implications. Expert Opin Invest Drugs 20(12):1665–1676

    Article  CAS  Google Scholar 

  19. Salih FA, Kaushik NK, Sharma P, Choudary GV, Murthy PS, Venkitasubramanian TA (1991) Calmodulin-like activity in mycobacteria. Indian J Biochem Biophys 28(5–6):491–495

    CAS  Google Scholar 

  20. Michalak K, Wesolowska O, Motohashi N, Molnar J, Hendrich AB (2006) Interactions of phenothiazines with lipid bilayer and their role in multidrug resistance reversal. Curr Drug Targets 7(9):1095–1105

    Article  CAS  Google Scholar 

  21. Langerman L, Bansinath M, Grant GJ (1994) The partition coefficient as a predictor of local anesthetic potency for spinal anesthesia: evaluation of five local anesthetics in a mouse model. Anesth Analg 79(3):490–494

    Article  CAS  Google Scholar 

  22. Forrest FM, Forrest IS, Roizin L (1963) Clinical, biochemical and post mortem studies on a patient treated with chlorpromazine. Agressologie 4:259–265

    CAS  Google Scholar 

  23. Sachlos E, Risueno RM, Laronde S, Shapovalova Z, Lee JH, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M (2012) Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149(6):1284–1297. doi:10.1016/j.cell.2012.03.049

    Article  CAS  Google Scholar 

  24. Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188(4194):1217–1219

    Article  CAS  Google Scholar 

  25. Carlo RD, Muccioli G, Bellussi G, Portaleone P, Ghi P, Racca S, Carlo FD (1986) Steroid, prolactin, and dopamine receptors in normal and pathologic breast tissue. Ann NY Acad Sci 464(1):559–562. doi:10.1111/j.1749-6632.1986.tb16068.x

    Article  Google Scholar 

  26. Peters GH, Wang C, Cruys-Bagger N, Velardez GF, Madsen JJ, Westh P (2013) Binding of serotonin to lipid membranes. J Am Chem Soc 135(6):2164–2171. doi:10.1021/ja306681d

    Article  CAS  Google Scholar 

  27. Jodko-Piorecka K, Litwinienko G (2013) First experimental evidence of dopamine interactions with negatively charged model biomembranes. ACS Chem Neurosci. doi:10.1021/cn4000633

    Google Scholar 

  28. Orlowski A, Grzybek M, Bunker A, Pasenkiewicz-Gierula M, Vattulainen I, Mannisto PT, Rog T (2012) Strong preferences of dopamine and l-dopa towards lipid head group: importance of lipid composition and implication for neurotransmitter metabolism. J Neurochem 122(4):681–690. doi:10.1111/j.1471-4159.2012.07813.x

    Article  CAS  Google Scholar 

  29. Amaral L, Kristiansen JE, Viveiros M, Atouguia J (2001) Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J Antimicrob Chemother 47(5):505–511

    Article  CAS  Google Scholar 

  30. Castaing M, Brouant P, Loiseau A, Santelli-Rouvier C, Santelli M, Alibert-Franco S, Mahamoud A, Barbe J (2000) Membrane permeation by multidrug-resistance-modulators and non-modulators: effects of hydrophobicity and electric charge. J Pharm Pharmacol 52(3):289–296

    Article  CAS  Google Scholar 

  31. Gulyaeva N, Zaslavsky A, Lechner P, Chlenov M, McConnell O, Chait A, Kipnis V, Zaslavsky B (2003) Relative hydrophobicity and lipophilicity of drugs measured by aqueous two-phase partitioning, octanol-buffer partitioning and HPLC. A simple model for predicting blood-brain distribution. Eur J Med Chem 38(4):391–396

    Article  CAS  Google Scholar 

  32. Christensen JB, Hendricks O, Chaki S, Mukherjee S, Das A, Pal TK, Dastidar SG, Kristiansen JE (2013) A comparative analysis of in vitro and in vivo efficacies of the enantiomers of thioridazine and its racemate. PLoS One 8(3):e57493. doi:10.1371/journal.pone.0057493

    Article  CAS  Google Scholar 

  33. Berger O, Edholm O, Jahnig F (1997) Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys J 72(5):2002–2013. doi:10.1016/s0006-3495(97)78845-3

    Article  CAS  Google Scholar 

  34. Bachar M, Brunelle P, Tieleman DP, Rauk A (2004) Molecular dynamics simulation of a polyunsaturated lipid bilayer susceptible to lipid peroxidation. J Phys Chem B 108(22):7170–7179. doi:10.1021/Jp036981u

    Article  CAS  Google Scholar 

  35. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) Interaction models for water in relation to protein hydration. Intermolecular Forces 14:331–342

    Google Scholar 

  36. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Laham A, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03. Gaussian, Inc., Wallingford, CT

  37. Van Gunsteren WF, Berendsen HJC (1987) Groningen molecular simulation (GROMOS). Library manual, Biomos, Groningen, The Netherlands, p 1–221

  38. van Buuren AR, Marrink SJ, Berendsen HJC (1993) A molecular dynamics study of the decane/water interface. J Phys Chem 97(36):9206–9212. doi:10.1021/j100138a023

    Article  Google Scholar 

  39. Mark AE, van Helden SP, Smith PE, Janssen LHM, van Gunsteren WF (1994) Convergence properties of free energy calculations: alpha.-cyclodextrin complexes as a case study. J Am Chem Soc 116(14):6293–6302. doi:10.1021/ja00093a032

    Article  CAS  Google Scholar 

  40. Khandelia H, Witzke S, Mouritsen OG (2010) Interaction of salicylate and a terpenoid plant extract with model membranes: reconciling experiments and simulations. Biophys J 99(12):3887–3894. doi:10.1016/j.bpj.2010.11.009

    Article  CAS  Google Scholar 

  41. Lindahl E, Hess B, van der Spoel D (2001) GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7(8):306–317

    CAS  Google Scholar 

  42. Leach AR (2001) Molecular modeling principles and applications, 2nd edn. Pearson Education Limited, p 356

  43. Hess B (2008) P-LINCS: a parallel linear constraint solver for molecular simulation. J Chem Theory Comput 4(1):116–122

    Article  CAS  Google Scholar 

  44. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98(12):10089–10092

    Article  CAS  Google Scholar 

  45. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103(19):8577–8593

    Article  CAS  Google Scholar 

  46. Berendsen HJC, Postma JPM, Van Gunsteren WF, Dinola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81(8):3684–3690

    Article  CAS  Google Scholar 

  47. Lindahl E, Edholm O (2000) Spatial and energetic–entropic decomposition of surface tension in lipid bilayers from molecular dynamics simulations. J Chem Phys 113(9):3882–3893

    Article  CAS  Google Scholar 

  48. Irving JH, Kirkwood JG (1950) The statistical mechanical theory of transport processes. IV. The equations of hydrodynamics. J Chem Phys 18(6):817–829

    Article  CAS  Google Scholar 

  49. Terama E, Ollila OHS, Salonen E, Rowat AC, Trandum C, Westh P, Patra M, Karttunen M, Vattulainen I (2008) Influence of ethanol on lipid membranes: from lateral pressure profiles to dynamics and partitioning. J Phys Chem B 112(13):4131–4139

    Article  CAS  Google Scholar 

  50. Jerabek H, Pabst G, Rappolt M, Stockner T (2010) Membrane-mediated effect on ion channels induced by the anesthetic drug ketamine. J Am Chem Soc 132(23):7990–7997. doi:10.1021/ja910843d

    Article  CAS  Google Scholar 

  51. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38

    Article  CAS  Google Scholar 

  52. Marrink SJ, Berendsen HJC (1996) Permeation process of small molecules across lipid membranes studied by molecular dynamics simulations. J Phys Chem 100(41):16729–16738

    Article  CAS  Google Scholar 

  53. Pautot S, Frisken BJ, Weitz DA (2003) Engineering asymmetric vesicles. Proc Natl Acad Sci USA 100(19):10718–10721. doi:10.1073/pnas.1931005100

    Article  CAS  Google Scholar 

  54. Abu-Baker S, Qi X, Lorigan GA (2007) Investigating the interaction of Saposin C with POPS and POPC phospholipids: a solid-state NMR spectroscopic study. Biophys J 93(10):3480–3490

    Article  CAS  Google Scholar 

  55. Mukhopadhyay P, Monticelli L, Tieleman DP (2004) Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl. Biophys J 86(3):1601–1609

    Article  CAS  Google Scholar 

  56. Ferreira TM, Coreta-Gomes F, Samuli Ollila OH, Moreno MJ, Vaz WLC, Topgaard D (2013) Cholesterol and POPC segmental order parameters in lipid membranes: solid state 1H–13C NMR and MD simulation studies. Phys Chem Chem Phys 15(6):1976–1989

    Article  CAS  Google Scholar 

  57. Bagatolli LA, Ipsen JH, Simonsen AC, Mouritsen OG (2010) An outlook on organization of lipids in membranes: searching for a realistic connection with the organization of biological membranes. Prog Lipid Res 49(4):378–389

    Article  CAS  Google Scholar 

  58. Bagatolli LA, Mouritsen OG (2013) Is the fluid mosaic (and the accompanying raft hypothesis) a suitable model to describe fundamental features of biological membranes? What may be missing? Front Plant Sci 4:457. doi:10.3389/fpls.2013.00457

    Article  Google Scholar 

  59. Cournia Z, Ullmann GM, Smith JC (2007) Differential effects of cholesterol, ergosterol and lanosterol on a dipalmitoyl phosphatidylcholine membrane: a molecular dynamics simulation study. J Phys Chem B 111(7):1786–1801

    Article  CAS  Google Scholar 

  60. Epand RM, Epand RF (2011) Bacterial membrane lipids in the action of antimicrobial agents. J Pept Sci 17(5):298–305. doi:10.1002/psc.1319

    Article  CAS  Google Scholar 

  61. Riedl S, Rinner B, Asslaber M, Schaider H, Walzer S, Novak A, Lohner K, Zweytick D (2011) In search of a novel target—phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim Biophys Acta 1808(11):2638–2645. doi:10.1016/j.bbamem.2011.07.026

    Article  CAS  Google Scholar 

  62. Milutinovic PS, Yang L, Cantor RS, Eger EI II, Sonner JM (2007) Anesthetic-like modulation of a gamma-aminobutyric acid type A, strychnine-sensitive glycine, and N-methyl-d-aspartate receptors by coreleased neurotransmitters. Anesth Analg 105(2):386–392. doi:10.1213/01.ane.0000267258.17197.7d

    Article  CAS  Google Scholar 

  63. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9(2):112–124. doi:10.1038/nrm2330

    Article  Google Scholar 

  64. Denisov G, Wanaski S, Luan P, Glaser M, McLaughlin S (1998) Binding of basic peptides to membranes produces lateral domains enriched in the acidic lipids phosphatidylserine and phosphatidylinositol 4,5-bisphosphate: an electrostatic model and experimental results. Biophys J 74(2 Pt 1):731–744. doi:10.1016/s0006-3495(98)73998-0

    Article  CAS  Google Scholar 

  65. Leventis PA, Grinstein S (2010) The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 39:407–427. doi:10.1146/annurev.biophys.093008.131234

    Article  CAS  Google Scholar 

  66. Witzke S, Duelund L, Kongsted J, Petersen M, Mouritsen OG, Khandelia H (2010) Inclusion of terpenoid plant extracts in lipid bilayers investigated by molecular dynamics simulations. J Phys Chem B 114(48):15825–15831

    Article  CAS  Google Scholar 

  67. Frenzel J, Arnold K, Nuhn P (1978) Calorimetric, 13C NMR, and 31P NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. Biochim Biophys Acta Biomembr 507(2):185–197

    Article  CAS  Google Scholar 

  68. Lichtenberger LM, Zhou Y, Jayaraman V, Doyen JR, O’Neil RG, Dial EJ, Volk DE, Gorenstein DG, Boggara MB, Krishnamoorti R (2012) Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine. Biochim Biophys Acta 1821(7):994–1002. doi:10.1016/j.bbalip.2012.04.002

    Article  CAS  Google Scholar 

  69. Parry MJ, Alakoskela JMI, Khandelia H, Kumar SA, Jäättelä M, Mahalka AK, Kinnunen PKJ (2008) High-affinity small molecule-phospholipid complex formation: binding of siramesine to phosphatidic acid. J Am Chem Soc 130(39):12953–12960

    Article  CAS  Google Scholar 

  70. MacCallum JL, Tieleman DP (2008) Interactions between small molecules and lipid bilayers. Curr Top Membr 60:227–256. doi:10.1016/S1063-5823(08)00008-2

    Article  CAS  Google Scholar 

  71. Rog T, Pasenkiewicz-Gierula M, Vattulainen I, Karttunen M (2009) Ordering effects of cholesterol and its analogues. Biochim Biophys Acta 1788(1):97–121. doi:10.1016/j.bbamem.2008.08.022

    Article  CAS  Google Scholar 

  72. Edholm O, Nagle JF (2005) Areas of molecules in membranes consisting of mixtures. Biophys J 89(3):1827–1832. doi:10.1529/biophysj.105.064329

    Article  CAS  Google Scholar 

  73. Hermetter A, Kopec W, Khandelia H (2013) Conformations of double-headed, triple-tailed phospholipid oxidation lipid products in model membranes. Biochim Biophys Acta 1828:1700–1706. doi:10.1016/j.bbamem.2013.03.030

    Article  CAS  Google Scholar 

  74. Hendrich AB, Wesołowska O, Komorowska M, Motohashi N, Michalak K (2002) The alterations of lipid bilayer fluidity induced by newly synthesized phenothiazine derivative. Biophys Chem 98(3):275–285

    Article  CAS  Google Scholar 

  75. Dobrzynska I, Szachowicz-Petelska B, Sulkowski S, Figaszewski Z (2005) Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol Cell Biochem 276(1–2):113–119. doi:10.1007/s11010-005-3557-3

    Article  CAS  Google Scholar 

  76. Cantor RS (2003) Receptor desensitization by neurotransmitters in membranes: are neurotransmitters the endogenous anesthetics? Biochemistry 42(41):11891–11897

    Article  CAS  Google Scholar 

  77. Samuli Ollila OH, Rog T, Karttunen M, Vattulainen I (2007) Role of sterol type on lateral pressure profiles of lipid membranes affecting membrane protein functionality: comparison between cholesterol, desmosterol, 7-dehydrocholesterol and ketosterol. J Struct Biol 159(2):311–323. doi:10.1016/j.jsb.2007.01.012

    Article  CAS  Google Scholar 

  78. Lau AY, Roux B (2007) The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain. Structure 15(10):1203–1214. doi:10.1016/j.str.2007.07.015

    Article  CAS  Google Scholar 

Download references

Acknowledgments

MEMPHYS - Center for Biomembrane Physics is supported by the Danish National Research Foundation. The computations were done at the SDU node of the Danish Center for Scientific Computing (DCSC). Himanshu Khandelia is funded by a Lundbeck Junior Group Leader Investigator Fellowship. We thank Emppu Salonen for the QM/MM calculations and the parametrization of THZ molecule. We also thank Jette Kristiansen for helpful discussions.

Author information

Authors and Affiliations

  1. MEMPHYS - Center for Biomembrane Physics, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark

    Wojciech Kopec & Himanshu Khandelia

Authors
  1. Wojciech Kopec
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Himanshu Khandelia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Himanshu Khandelia.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1019 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kopec, W., Khandelia, H. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations. J Comput Aided Mol Des 28, 123–134 (2014). https://doi.org/10.1007/s10822-014-9737-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-014-9737-z

Keywords

Search

Navigation