In Silico Pharmacology

, 6:6 | Cite as

Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting β-lactamase of Mycobacterium tuberculosis

  • Md. Junaid
  • Md. Jahangir Alam
  • Md. Kamal Hossain
  • Mohammad A. Halim
  • M. Obayed Ullah
Original Research


In recent years, multidrug-resistance has become a primary concern in the treatment and management of tuberculosis, an infectious disease caused by Mycobacterium tuberculosis. In this context, searching new anti-tuberculosis agents particularly targeting the β-lactamase (BlaC) is reported to be promising as this enzyme is one of the key player in the development of multidrug resistance. This study reports the design of some Nickel (Ni) based tetradentate N2O2 Schiff bases, employing density functional theory. All analogs are optimized at B3LYP/SDD level of theory. Dipole moment, electronic energy, enthalpy, Gibbs free energy, HOMO–LUMO gap, and softness of these modified drugs are also investigated. Molecular interactions between designed ligands and BlaC have been analyzed by molecular docking approach, followed by molecular dynamics (MD) simulation. All designed compounds show low HOMO–LUMO gap, while addition of halogen increases the dipole moment of the compounds. Docking and MD simulation investigations reveal that the designed compounds are more potent than standard inhibitor, where Ile117, Pro290, Arg236 and Thr253 residues of BlaC are found to play important role in the ligand binding. Through MD simulation study, the best binding compound is also observed to form stable complex by increasing the protein rigidness. The ADME/T analysis suggests that modified drugs are less toxic and shows an improved pharmacokinetic properties than that of the standard drug. These results further confirm the ability of Ni-directed Schiff bases to bind simultaneously to the active site of BlaC and support them as potential candidates for the future treatment of tuberculosis disease.


Tuberculosis Anti-microbial activity Schiff base Density functional theory (DFT) Molecular dynamics ADME/T 


  1. Aboul-Fadl T, Mohammed FA-H, Hassan EA-S (2003) Synthesis, antitubercular activity and pharmacokinetic studies of some Schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH). Arch Pharm Res 26:778–784CrossRefPubMedGoogle Scholar
  2. Abu-Khadra AS, Farag RS, Abdel-Hady AEDM (2016) Synthesis, characterization and antimicrobial activity of Schif base (E)-N-(4-(2-hydroxybenzylideneamino)phenylsulfonyl) acetamide metal complexes. Am J Anal Chem 7:233–245CrossRefGoogle Scholar
  3. Ali SMM, Azad MAK, Jesmin M, Ahsan S, Rahman MM, Khanam JA et al (2012) In vivo anticancer activity of vanillin semicarbazone. Asian Pac J Trop Biomed 2:438–442CrossRefPubMedPubMedCentralGoogle Scholar
  4. Avaji PG, Kumar CV, Patil SA, Shivananda K, Nagaraju C (2009) Synthesis, spectral characterization, in vitro microbiological evaluation and cytotoxic activities of novel macrocyclic bis hydrazone. Eur J Med Chem 44:3552–3559CrossRefPubMedGoogle Scholar
  5. Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A 38:3098CrossRefGoogle Scholar
  6. Bergner A, Dolg M, Küchle W, Stoll H, Preuß H (1993) Ab initio energy-adjusted pseudopotentials for elements of groups 13–17. Mol Phys 80:1431–1441CrossRefGoogle Scholar
  7. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H et al (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefPubMedPubMedCentralGoogle Scholar
  8. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM et al (2005) The amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chandramouli C, Shivanand M, Nayanbhai T, Bheemachari B, Udupi R (2012) Synthesis and biological screening of certain new triazole Schiff bases and their derivatives bearing substituted benzothiazole moiety. J Chem Pharm Res 4:1151–1159Google Scholar
  10. Chaubey A, Pandeya S (2012) Synthesis & anticonvulsant activity (Chemo Shock) of Schiff and Mannich bases of Isatin derivatives with 2-Amino pyridine (mechanism of action). Int J PharmTech Res 4:590–598Google Scholar
  11. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G et al (2012) admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. ACS Publications, Washington, DCGoogle Scholar
  12. Chinnasamy RP, Sundararajan R, Govindaraj S (2010) Synthesis, characterization, and analgesic activity of novel schiff base of isatin derivatives. J Adv Pharma Technol Res 1:342CrossRefGoogle Scholar
  13. Connolly LE, Edelstein PH, Ramakrishnan L (2007) Why is long-term therapy required to cure tuberculosis? PLoS Med 4:e120CrossRefPubMedPubMedCentralGoogle Scholar
  14. Corbeil CR, Williams CI, Labute P (2012) Variability in docking success rates due to dataset preparation. J Comput Aided Mol Des 26:775–786CrossRefPubMedPubMedCentralGoogle Scholar
  15. da Silva CM, da Silva DL, Modolo LV, Alves RB, de Resende MA, Martins CVB et al (2011) Schiff bases: a short review of their antimicrobial activities. J Adv Res 2:1–8CrossRefGoogle Scholar
  16. Dash R, Hosen S, Sultana T, Junaid M, Majumder M, Ishat IA et al (2016) Computational analysis and binding site identification of type III secretion system ATPase from Pseudomonas aeruginosa. Interdiscip Sci, Comput Life Sci 8:403–411CrossRefGoogle Scholar
  17. Edwards JR, Betts MJ (2000) Carbapenems: the pinnacle of the β-lactam antibiotics or room for improvement? J Antimicrob Chemother 45:1–4CrossRefPubMedGoogle Scholar
  18. Egan WJ, Merz KM, Baldwin JJ (2000) Prediction of drug absorption using multivariate statistics. J Med Chem 43:3867–3877CrossRefPubMedGoogle Scholar
  19. Emran TB, Rahman MA, Uddin MMN, Dash R, Hossen MF, Mohiuddin M et al (2015) Molecular docking and inhibition studies on the interactions of Bacopa monnieri’s potent phytochemicals against pathogenic Staphylococcus aureus. DARU J Pharm Sci 23:26CrossRefGoogle Scholar
  20. Feiler C, Fisher AC, Boock JT, Marrichi MJ, Wright L, Schmidpeter PA et al (2013) Directed evolution of Mycobacterium tuberculosis β-lactamase reveals gatekeeper residue that regulates antibiotic resistance and catalytic efficiency. PLoS ONE 8:e73123CrossRefPubMedPubMedCentralGoogle Scholar
  21. Flores AR, Parsons LM, Pavelka MS Jr (2005a) Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics. Microbiology 151:521–532CrossRefPubMedGoogle Scholar
  22. Flores AR, Parsons LM, Pavelka MS (2005b) Characterization of novel Mycobacterium tuberculosis and Mycobacterium smegmatis mutants hypersusceptible to β-lactam antibiotics. J Bacteriol 187:1892–1900CrossRefPubMedPubMedCentralGoogle Scholar
  23. Harrison JW, Svec TA (1998) The beginning of the end of the antibiotic era? Part I. The problem: abuse of the” miracle drugs”. Quintessence Int 29:151–162PubMedGoogle Scholar
  24. Hayhurst EJ, Kailas L, Hobbs JK, Foster SJ (2008) Cell wall peptidoglycan architecture in Bacillus subtilis. Proc Natl Acad Sci 105:14603–14608CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hearn MJ, Cynamon MH (2004) Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base. J Antimicrob Chemother 53:185–191CrossRefPubMedGoogle Scholar
  26. Hoque MM, Halim MA, Sarwar MG, Khan M (2015) Palladium-catalyzed cyclization of 2-alkynyl-N-ethanoyl anilines to indoles: synthesis, structural, spectroscopic, and mechanistic study. J Phys Org Chem 28:732–742CrossRefGoogle Scholar
  27. Kajal A, Bala S, Kamboj S, Sharma N, Saini V (2013) Schif bases: a versatile pharmacophore. J Catal 2013:893512Google Scholar
  28. Krieger E, Vriend G (2015) New ways to boost molecular dynamics simulations. J Comput Chem 36:996–1007CrossRefPubMedGoogle Scholar
  29. Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G (2004) Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins Struct Funct Bioinf 57:678–683. CrossRefGoogle Scholar
  30. Krieger E, Nielsen JE, Spronk CA, Vriend G (2006) Fast empirical pKa prediction by Ewald summation. J Mol Graph Model 25:481–486CrossRefPubMedGoogle Scholar
  31. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785CrossRefGoogle Scholar
  32. Lien EJ, Guo ZR, Li RL, Su CT (1982) Use of dipole moment as a parameter in drug-receptor interaction and quantitative structure-activity relationship studies. J Pharm Sci 71:641–655CrossRefPubMedGoogle Scholar
  33. Meroueh SO, Fisher JF, Schlegel HB, Mobashery S (2005) Ab initio QM/MM study of class A β-lactamase acylation: dual participation of Glu166 and Lys73 in a concerted base promotion of Ser70. J Am Chem Soc 127:15397–15407CrossRefPubMedGoogle Scholar
  34. Miri R, Razzaghi-asl N, Mohammadi MK (2013) QM study and conformational analysis of an isatin Schiff base as a potential cytotoxic agent. J Mol Model 19(2):727–735Google Scholar
  35. Mishra S, Shukla P, Bhaskar A, Anand K, Baloni P, Jha RK et al (2017) Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis. eLife 6:e25624PubMedPubMedCentralGoogle Scholar
  36. Mounika K, Pragathi A, Gyanakumari C (2010) Synthesis characterization and biological activity of a Schiff base derived from 3-ethoxy salicylaldehyde and 2-amino benzoic acid and its transition metal complexes. J Sci Res 2:513Google Scholar
  37. Pandey A, Dewangan D, Verma S, Mishra A, Dubey R (2011) Synthesis of schiff bases of 2-amino-5-aryl-1, 3, 4-thiadiazole and its analgesic, anti-inflammatory, antibacterial and antitubercular activity. Int J Chem Tech Res 3:178–184Google Scholar
  38. Parr RG, Yang W (1989) Density-functional theory of atoms and molecules. Oxford University Press, New YorkGoogle Scholar
  39. Parr RG, Zhou Z (1993) Absolute hardness: unifying concept for identifying shells and subshells in nuclei, atoms, molecules, and metallic clusters. Acc Chem Res 26:256–258CrossRefGoogle Scholar
  40. Pearson RG (1986) Absolute electronegativity and hardness correlated with molecular orbital theory. Proc Natl Acad Sci 83:8440–8441CrossRefPubMedPubMedCentralGoogle Scholar
  41. Sathe BS, Jaychandran E, Jagtap V, Sreenivasa G (2011) Synthesis characterization and anti-inflammatory evaluation of new fluorobenzothiazole schiff’s bases. Int J Pharm Res Dev 3:164–169Google Scholar
  42. Sondhi SM, Singh N, Kumar A, Lozach O, Meijer L (2006) Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff’s bases. Bioorganic Med Chem 14:3758–3765CrossRefGoogle Scholar
  43. Souza AOD, Galetti F, Silva CL, Bicalho B, Parma MM, Fonseca SF et al (2007) Antimycobacterial and cytotoxicity activity of synthetic and natural compounds. Química Nova 30:1563–1566Google Scholar
  44. Susnow RG, Dixon SL (2003) Use of robust classification techniques for the prediction of human cytochrome P450 2D6 inhibition. J Chem Inform Comput Sci 43:1308–1315CrossRefGoogle Scholar
  45. Tessema B, Nabeta P, Valli E, Albertini A, Collantes J, Lan NH et al (2017) FIND tuberculosis strain bank: a resource for researchers and developers working on tests to detect Mycobacterium tuberculosis and related drug resistance. J Clin Microbiol 55:1066–1073CrossRefPubMedPubMedCentralGoogle Scholar
  46. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461PubMedPubMedCentralGoogle Scholar
  47. Venkatesh P (2011) Synthesis, characterization and antimicrobial activity of various schiff bases complexes of Zn (II) and Cu (II) ions. Asian J Pharm Hea Sci 1:8–11Google Scholar
  48. Wang F, Cassidy C, Sacchettini JC (2006) Crystal structure and activity studies of the Mycobacterium tuberculosis β-lactamase reveal its critical role in resistance to β-lactam antibiotics. Antimicrob Agents Chemother 50:2762–2771CrossRefPubMedPubMedCentralGoogle Scholar
  49. Wei D, Li N, Lu G, Yao K (2006) Synthesis, catalytic and biological activity of novel dinuclear copper complex with Schiff base. Sci Chin Ser B Chem 49:225–229CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesNorth South UniversityDhakaBangladesh
  2. 2.Department of ChemistryJahangirnagar UniversityDhakaBangladesh
  3. 3.Division of Computer-Aided Drug DesignThe Red-Green Research Centre, BICCBDhakaBangladesh
  4. 4.Université de Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière MatièreLyonFrance

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