SpringerLink
Log in

Structure-based virtual screening, molecular docking and dynamics studies of natural product and classical inhibitors against human dihydrofolate reductase

  • Original Article
  • Published:
Network Modeling Analysis in Health Informatics and Bioinformatics Aims and scope Submit manuscript

Abstract

Folate antagonists are classified as important and valuable therapeutic agents against infection, neoplastic, and inflammatory diseases. Dihydrofolate reductase (DHFR) is a biological target of two well-defined folate antagonists, classical and non-classical inhibitors. DHFR catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate benefits of NADPH as a cofactor. With the point to recognize new chemicals to be utilized for further structure-based drug design, a collection of 67753 molecules including chemicals and natural products have been screened through the docking method from the Zinc Database. The high ranked compound with regard to methotrexate (MTX), resulted to be three compounds comprises of ZINC29236925, ZINC31169388, and ZINC01629864, which further investigated by molecular dynamics (MD) simulation, Poisson–Boltzmann surface area method (MM-PBSA) and QMMM calculations. PCA analysis revealed that upon inhibitor binding, the DHFR folding is changed. Our QMMM data suggested that a structure with ZINC ID of ZINC31169388 has a stronger interaction with DHFR active site and could be a favorable candidacy for biological assessment and additional advanced improvement. Furthermore, ADMET prediction illustrated that all physicochemical factors of ZINC31169388 are within the satisfactory span described for human treatment.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  • Ajay Bemis GW, Murcko MA (1999) Designing libraries with CNS activity. J Med Chem 42:4942–4951

    Google Scholar 

  • Arai M, Kondrashkina E, Kayatekin C, Matthews CR, Iwakura M, Bilsel O (2007) Microsecond hydrophobic collapse in the folding of Escherichia coli dihydrofolate reductase, an α/β-type protein. J Mol Biol 368:219–229

    Google Scholar 

  • Arooj M, Thangapandian S, John S, Hwang S, Park JK, Lee KW (2011) 3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors. Int J Mol Sci 12:9236–9264

    Google Scholar 

  • Arora K, Brooks Iii CL (2009) Functionally important conformations of the Met20 loop in dihydrofolate reductase are populated by rapid thermal fluctuations. J Am Chem Soc 131:5642–5647

    Google Scholar 

  • Banerjee P, Eckert AO, Schrey AK, Preissner R (2018) ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 46:W257–W263

    Google Scholar 

  • Bas DC, Rogers DM, Jensen JH (2008) Very fast prediction and rationalization of pKa values for protein–ligand complexes. Proteins Struct Funct Bioinform 73:765–783

    Google Scholar 

  • Bebrone C, Lassaux P, Vercheval L, Sohier J-S, Jehaes A, Sauvage E et al (2010) Current challenges in antimicrobial chemotherapy. Drugs 70:651–679

    Google Scholar 

  • Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Google Scholar 

  • Bolin JT, Filman DJ, Matthews DA, Hamlin RC, Kraut J (1982) Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. J Biol Chem 257:13650–13662

    Google Scholar 

  • Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101

    Google Scholar 

  • Calvert H (2003) Pemetrexed (Alimta): a promising new agent for the treatment of breast cancer. Semin Oncol 30(2 Suppl 3):2–5. https://doi.org/10.1053/sonc.2003.37267

  • Carlson HA, Jorgensen WL (1995) An extended linear response method for determining free energies of hydration. J Phys Chem 99:10667–10673

    Google Scholar 

  • Cavalli A, Poluzzi E, De Ponti F, Recanatini M (2002) Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K+ channel blockers. J Med Chem 45:3844–3853

    Google Scholar 

  • Chen M-J, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J et al (1984) The functional human dihydrofolate reductase gene. J Biol Chem 259:3933–3943

    Google Scholar 

  • Cheng T, Li Q, Zhou Z, Wang Y, Bryant SH (2012) Structure-based virtual screening for drug discovery: a problem-centric review. AAPS J 14:133–141

    Google Scholar 

  • Chu E, Takimoto CH, Voeller D, Grem JL, Allegra CJ (1993) Specific binding of human dihydrofolate reductase protein to dihydrofolate reductase messenger RNA in vitro. Biochemistry 32:4756–4760

    Google Scholar 

  • Cody V, Luft J, Ciszak E, Kalman T, Freisheim J (1992) Crystal structure determination at 2.3 A of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-gamma-tetrazole. Anti Cancer Drug Des 7:483–491

    Google Scholar 

  • Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL (1997) Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523. Biochemistry 36:13897–13903

    Google Scholar 

  • Cody V, Luft JR, Pangborn W (2005) Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH. Acta Crystallogr D Biol Crystallogr 61:147–155

    Google Scholar 

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

    Google Scholar 

  • Elslager EF, Johnson JL, Werbel LM (1983) Folate antagonists. 20. Synthesis and antitumor and antimalarial properties of trimetrexate and related 6-[(phenylamino) methyl]-2,4-quinazolinediamines. J Med Chem 26:1753–1760

    Google Scholar 

  • Ercikan-Abali EA, Banerjee D, Waltham MC, Skacel N, Scotto KW, Bertino JR (1997) Dihydrofolate reductase protein inhibits its own translation by binding to dihydrofolate reductase mRNA sequences within the coding region. Biochemistry 36:12317–12322

    Google Scholar 

  • Essmann U, Perera L, Berkowitz ML (1995) The origin of the hydration interaction of lipid bilayers from MD simulation of dipalmitoylphosphatidylcholine membranes in gel and liquid crystalline phases. Langmuir 11:4519–4531

    Google Scholar 

  • Felson DT, Chernoff M, Anderson J, Weinblatt M, Furst D, Schmid F et al (1995) The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 22:218–223

    Google Scholar 

  • Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228

    Google Scholar 

  • Genheden S, Ryde U (2015) The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 10:449–461

    Google Scholar 

  • Grivsky EM, Lee S, Sigel CW, Duch DS, Nichol CA (1980) Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. J Med Chem 23:327–329

    Google Scholar 

  • Günther S, Senger C, Michalsky E, Goede A, Preissner R (2006) Representation of target-bound drugs by computed conformers: implications for conformational libraries. BMC Bioinform 7:1

    Google Scholar 

  • Herfarth HH, Long MD, Isaacs KL (2013) Methotrexate: underused and ignored? Dig Dis 30:112–118

    Google Scholar 

  • Hess B, Bekker H, Berendsen HJ, Fraaije JG (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Google Scholar 

  • Hileman B (2006) Accounting for R&D-Many doubt the $800 million pharmaceutical price tag. Chem Eng News 84:50

    Google Scholar 

  • Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/GBSA methods: II. The accuracy of ranking poses generated from docking. J Comput Chem 32:866–877

    Google Scholar 

  • Hsu M-C, Chen C-C (2015) Low-dose methotrexate-induced ulcerated psoriatic plaques: a rare case. JAAD Case Rep 1:264–266

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA (1983) The pharmacology and clinical use of methotrexate. N Engl J Med 309:1094–1104

    Google Scholar 

  • Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Google Scholar 

  • Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236

    Google Scholar 

  • Karami M, Jalali C, Mirzaie S (2017) Combined virtual screening, MMPBSA, molecular docking and dynamics studies against deadly anthrax: an in silico effort to inhibit Bacillus anthracis nucleoside hydrolase. J Theor Biol 420:180–189

    Google Scholar 

  • Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen J-P (1999) Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 16:1514–1519

    Google Scholar 

  • Klon AE, Héroux A, Ross LJ, Pathak V, Johnson CA, Piper JR et al (2002) Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 Å and 1.05 Å resolution. J Mol Biol 320:677–693

    Google Scholar 

  • Kollman P (1993) Free energy calculations: applications to chemical and biochemical phenomena. Chem Rev 93:2395–2417

    Google Scholar 

  • Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L et al (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897

    Google Scholar 

  • Kovalevskaya NV, Smurnyy YD, Polshakov VI, Birdsall B, Bradbury AF, Frenkiel T et al (2005) Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH. J Biomol NMR 33:69–72

    Google Scholar 

  • Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR (1989) Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 110:353–356

    Google Scholar 

  • Kumar K, Anbarasu A, Ramaiah S (2014) Molecular docking and molecular dynamics studies on β-lactamases and penicillin binding proteins. Mol BioSyst 10:891–900

    Google Scholar 

  • Kumari R, Kumar R, Lynn A (2014) g_mmpbsa: a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54:1951–1962

    Google Scholar 

  • 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 37:785

    Google Scholar 

  • Luco JM (1999) Prediction of the brain–blood distribution of a large set of drugs from structurally derived descriptors using partial least-squares (PLS) modeling. J Chem Inf Comput Sci 39:396–404

    Google Scholar 

  • McElheny D, Schnell JR, Lansing JC, Dyson HJ, Wright PE (2005) Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis. Proc Natl Acad Sci USA 102:5032–5037

    Google Scholar 

  • Mirzaie S, Rafii F, Yasunaga K, Yoshunaga K, Sepehrizadeh Z, Kanno S et al (2012) Prediction of the mode of interaction between monoterpenes and the nitroreductase from Enterobacter cloacae by docking simulation. Comput Biol Med 42:414–421

    Google Scholar 

  • Mirzaie S, Najafi K, Hakhamaneshi MS, Shahverdi AR, Fathi F (2015) Investigation for antimicrobial resistance-modulating activity of diethyl malate and 1-methyl malate against beta-lactamase class A from Bacillus licheniformis by molecular dynamics, in vitro and in vivo studies. J Biomol Struct Dyn 33:1016–1026

    Google Scholar 

  • Mollica A, Mirzaie S, Costante R, Carradori S, Macedonio G, Stefanucci A et al (2015) Exploring the biological consequences of conformational changes in aspartame models containing constrained analogues of phenylalanine. J Enzym Inhib Med Chem 31(6):953–963. https://doi.org/10.3109/14756366.2015.1076811

  • Mullarkey M, Andrade W, Blumenstein B, Bailey G (1988) Methotrexate in the treatment of corticosteroid-dependent asthma: a double-blind crossover study with follow-up. J Allergy Clin Immunol 81:182

    Google Scholar 

  • Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:7182–7190

    Google Scholar 

  • Potts SJ, Edwards DJ, Hoffman R (2005) Challenges of target/compound data integration from disease to chemistry: a case study of dihydrofolate reductase inhibitors. Curr Drug Discov Technol 2:75–87

    Google Scholar 

  • Söderhjelm P, Kongsted J, Ryde U (2010) Ligand affinities estimated by quantum chemical calculations. J Chem Theory Comput 6:1726–1737

    Google Scholar 

  • Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG (2002) Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics. Proc Natl Acad Sci USA 99:13481–13486

    Google Scholar 

  • Rajamanikandan S, Jeyakanthan J, Srinivasan P (2017) Discovery of potent inhibitors targeting Vibrio harveyi LuxR through shape and e-pharmacophore based virtual screening and its biological evaluation. Microb Pathog 103:40–56

    Google Scholar 

  • Rodrigues T, Reker D, Schneider P, Schneider G (2016) Counting on natural products for drug design. Nat Chem 8:531–541

    Google Scholar 

  • Sawaya MR, Kraut J (1997) Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence. Biochemistry 36:586–603

    Google Scholar 

  • Searles G, McKendry R (1987) Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol 14:1164–1171

    Google Scholar 

  • Sompornpisut P, Wijitkosoom A, Parasuk V, Sirawaraporn W (2003) Molecular dynamics simulation of the human apo-dihydrofolate reductase: an investigation of an unstable enzyme. Mol Simul 29:111–121

    Google Scholar 

  • Stein RB, Hanauer SB (2000) Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf 23:429–448

    Google Scholar 

  • Sun H, Li Y, Shen M, Tian S, Xu L, Pan P et al (2014) Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring. Phys Chem Chem Phys 16:22035–22045

    Google Scholar 

  • Teramoto R, Fukunishi H (2007) Supervised consensus scoring for docking and virtual screening. J Chem Inf Model 47:526–534

    Google Scholar 

  • Tosso RD, Andujar SA, Gutierrez L, Angelina E, Rodríguez R, Nogueras M et al (2013) Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J Chem Inf Model 53:2018–2032

    Google Scholar 

  • 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 31:455–461

    Google Scholar 

  • Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

    Google Scholar 

  • Wang J, Wang W, Kollman PA, Case DA (2006a) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model 25:247–260

    Google Scholar 

  • Wang J, Hou T, Xu X (2006b) Recent advances in free energy calculations with a combination of molecular mechanics and continuum models. Curr Comput Aided Drug Des 2:287–306

    Google Scholar 

  • Weinblatt M (2003) Rheumatoid arthritis in 2003: where are we now with treatment? Ann Rheum Dis 62:ii94–ii96

    Google Scholar 

  • Weinstein GD, Goldfaden G, Frost P (1971) Methotrexate: mechanism of action on DNA synthesis in psoriasis. Arch Dermatol 104:236–243

    Google Scholar 

  • Yazdanian M, Glynn SL, Wright JL, Hawi A (1998) Correlating partitioning and Caco-2 cell permeability of structurally diverse small molecular weight compounds. Pharm Res 15:1490–1494

    Google Scholar 

  • Zhan D, Yu L, ** H, Guan S, Han W (2014) Molecular modeling and MM-PBSA free energy analysis of endo-1,4-β-xylanase from Ruminococcus albus 8. Int J Mol Sci 15:17284–17303

    Google Scholar 

  • Zhang D, Lazim R (2017) Application of conventional molecular dynamics simulation in evaluating the stability of apomyoglobin in urea solution. Sci Rep 7:44651

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran

    Elnaz Hosseininezhadian Koushki, Chiako Farshadfar, Bayazid Hasanpour, Babisandz Feyzi & Sako Mirzaie

  2. Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Solmaz Abolghasemi

  3. Dipartimento di Farmacia, Università di Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100, Chieti, Italy

    Adriano Mollica

  4. Semnan Biotechnology Research Center, Semnan University of Medical Sciences, Basij Blvd, Semnan, Iran

    Mojtaba Aghaeepoor

  5. Department of Biochemistry, Falavarjan Branch, Islamic Azad University, Isfahan, Iran

    Seyedeh Sara Moosavi

  6. Department of Cellular and Molecular Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran

    Fatemeh Abdi

Authors
  1. Elnaz Hosseininezhadian Koushki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Solmaz Abolghasemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriano Mollica
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mojtaba Aghaeepoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seyedeh Sara Moosavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chiako Farshadfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bayazid Hasanpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Babisandz Feyzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fatemeh Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sako Mirzaie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bayazid Hasanpour or Sako Mirzaie.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koushki, E.H., Abolghasemi, S., Mollica, A. et al. Structure-based virtual screening, molecular docking and dynamics studies of natural product and classical inhibitors against human dihydrofolate reductase. Netw Model Anal Health Inform Bioinforma 9, 49 (2020). https://doi.org/10.1007/s13721-020-00244-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13721-020-00244-9

Keywords

Search

Navigation