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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Exploring the Role of Water Molecules in the Ligand Binding Domain of PDE4B and PDE4D: Virtual Screening Based Molecular Docking of Some Active Scaffolds

Author(s): Priya Singh, Mitali Mishra, Shivangi Agarwal, Samaresh Sau, Arun K. Iyer* and Sushil K. Kashaw*

Volume 15, Issue 4, 2019

Page: [334 - 366] Pages: 33

DOI: 10.2174/1573409914666181105153543

Price: $65

Abstract

Background: The phosphodiesterase (PDE) is a superfamily represented by four genes: PDE4A, B,C, and D which cause the hydrolysis of phosphodiester bond of cAMP to yield inactive AMP. c-AMP catalyzing enzyme is predominant in inflammatory and immunomodulatory cells. Therapy to treat Chronic Obstructive Pulmonary Disease (COPD) with the use of PDE4 inhibitors is highly envisaged.

Objective: A molecular docking experiment with large dataset of diverse scaffolds has been performed on PDE4 inhibitors to analyze the role of amino acid responsible for binding and activation of the secondary transmitters. Apart from the general docking experiment, the main focus was to discover the role of water molecules present in the ligand-binding domain.

Methods: All the compounds were docked in the PDE4B and PDE4D active cavity to produce the free binding energy scores and spatial disposition/orientation of chemical groups of inhibitors around the cavity. Under uniform condition, the experiments were carried out with and without water molecules in the LBD. The exhaustive study was carried out on the Autodock 4.2 software and explored the role of water molecules present in the binding domain.

Results: In presence of water molecule, Roflumilast has more binding affinity (-8.48 Kcal/mol with PDE4B enzyme and -8.91 Kcal/mol with PDE4D enzyme) and forms two hydrogen bonds with Gln443 and Glu369 and amino acid with PDE4B and PDE4D enzymes respectively. While in absence of water molecule its binding affinity has decreased (-7.3 Kcal/mol with PDE4B enzyme and -5.17 Kcal/mol with PDE4D enzyme) as well as no H-bond interactions were observed. Similar observation was made with clinically tested molecules.

Conclusion: In protein-ligand binding interactions, appropriate selection of water molecules facilitated the ligand binding, which eventually enhances the efficiency as well as the efficacy of ligand binding.

Keywords: Phosphodiesterases, chronic obstructive pulmonary disease, drug-receptor interaction and docking, PDE4B and PDE4D, Molecular Docking, ligand binding.

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[1]
Brown, W.M. Treating COPD with PDE 4 inhibitors. Int. J. COPD, 2007, 2, 517-533.
[2]
Lee, J.; Lee, H.; Kim, J.A.; Rhee, C.K. Trend of cost and utilization of COPD medication in Korea. Int. J. COPD., 2017, 12, 27-33.
[3]
Fabbri, L.M.; Hurd, S.S. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur. Respir. J., 2003, 22, 1.
[4]
Dhamane, A.D.; Schwab, P.; Hopson, S. Association between adherence to medications for COPD and medications for other chronic conditions in COPD patients. Int. J. COPD., 2017, 12, 115-122.
[5]
Su, Y.; Long, C.; Yu, Q.; Zhang, J.; Wu, D.; Duan, Z. Global scientific collaboration in COPD research. Int. J. COPD., 2017, 12, 215-225.
[6]
Pauwels, R.A.; Buist, A.S.; Calverley, P.M.; Jenkins, C.R.; Hurd, S.S. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am. J. Respir. Crit. Care Med., 2001, 163, 1256-1276.
[7]
Agusti, A.G.; Noguera, A.; Sauleda, J.; Sala, E.; Pons, J.; Busquets, X. Systemic effects of chronic obstructive pulmonary disease. Eur. Respir. J., 2003, 21, 347-360.
[8]
Kodimuthali, A.; Jabaris, S.S.L.; Pal, M. Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. J. Med. Chem., 2008, 51, 5471-5489.
[9]
Jain, A.K.; Veerasamy, R.; Vaidya, A.; Kashaw, S.K.; Mourya, V.K.; Agrawal, R.K. QSAR analysis of B-ring-modified diaryl ether derivatives as a InhA inhibitors. Med. Chem. Res., 2012, 21, 145-151.
[10]
Vaidya, A.; Jain, A.K.; Kumar, B.P.R.; Kashaw, S.K.; Agrawal, R.K. Predicting anti-cancer activity of quinoline derivatives: CoMFA and CoMSIA approach. J. Enzyme Inhib. Med. Chem., 2011, 26, 854-861.
[11]
Bhatiya, R.; Vaidya, A.; Kashaw, S.K.; Jain, A.K.; Agrawal, R.K. QSAR analysis of furanone derivatives as potential COX-2 inhibitor: kNN MFA approach. J. Saudi Chem. Soc., 2014, 18, 997-984.
[12]
Jain, S.; Vaidya, A.; Jain, A.K.; Agrawal, R.K.; Kashaw, S.K. Computational analysis of benzyl vinylogus derivatives as potent PDE3B inhibitor. Arab. J. Chem., 2017, 10, S109-S113.
[13]
Bissantz, C.; Flokers, G.; Rognan, D. Protein-based virtual screening of chemical database and evaluation of different docking/ scoring combinations. J. Med. Chem., 2000, 43, 4759-4767.
[14]
Alexander, R.P.; Warrellow, G.J.; Eaton, M.A. CDP840. A prototype of a novel class of orally active anti-inflammatory Phosphodiesterase 4 inhibitors. Bioorg. Med. Chem. Lett., 2002, 37, 64-69.
[15]
Vestbo, J.; Tan, L.; Atkinson, G.; Ward, J. A controlled trial of 6- weeks’ treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur. Respir. J., 2009, 33, 1039-1044.
[16]
Ochiai, H.; Ishida, A.; Ohtani, T. Discovery of new orally active phosphodiesterase (PDE4) inhibitors. Chem. Pharm. Bull., 2004, 52, 1098-1104.
[17]
Hulme, C.; Mathew, R.; Moriarty, K.; Miller, B. Orally active indole N-oxide PDE4 inhibitors. Bioorg. Med. Chem. Lett., 1998, 8, 3053-3058.
[18]
Kim, E.; Chun, H.O.; Jung, S.H. Improvement of therapeutic index of phosphodiesterase type IV inhibitors as anti- asthmatics. Bioorg. Med. Chem. Lett., 2003, 13, 2355-2358.
[19]
Buckley, G.; Cooper, N.; Hazel, J. 7-Methoxyfuran-4-carboxamides as PDE4 inhibitors: A potential treatment for asthma. Bioorg. Med. Chem. Lett., 2000, 10, 2137-2140.
[20]
Ochiai, H.; Ohtani, T.; Ishida, A. Highly potent PDE4 inhibitors with therapeutic potential. Bioorg. Med. Chem. Lett., 2004, 14, 207-210.
[21]
Brullo, C.; Massa, M.; Rocca, M. Synthesis, biological evaluation, and molecular modeling of new 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) related Phosphodiesterase 4D (PDE4D) inhibitors. J. Med. Chem., 2014, 57, 7061-7072.
[22]
Chakraborti, A.K.; Gopalakrishnan, B.; Sobhia, E.; Malde, A. 3D-QSAR studies of indole derivatives as PDE4 inhibitors. Eur. J. Med. Chem., 2003, 38, 975-982.
[23]
Savi, C.D.; Cox, D.J.; Warner, D. Efficacious inhaled pde4 inhibitors with low emetic potential and long duration of action for the treatment of COPD. J. Med. Chem., 2014, 57, 4661-4676.
[24]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30, 2785-2791.
[25]
Kuntz, D.I. Structure-based strategies for drug design and discovery. Science, 1992, 257, 1078-1082.
[26]
Drews, J. Drug discovery: A historical perspective. Science, 2000, 287, 1960-1964.
[27]
Sousa, S.F.; Fernandes, P.A.; Ramos, M.J. Protein-ligand docking: Current status and future challenges. Proteins Struct. Funct. Bioinf., 2006, 65, 15-26.
[28]
Tripos Associates, SYBYL X Molecular Modeling Software, Version 1.2, St. Louis.
[29]
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energyfunction. J. Comput. Chem., 1998, 19, 1639-1662.
[30]
Gasteiger, J.; Rudolph, C.; Sadowski, J. Automatic generation of 3D-atomic coordinates for organic molecules. Tetrahedron Comput. Methods, 1990, 3, 537-547.
[31]
Cui, D.W.X. Evaluation of PDE4 inhibition for COPD. Int. J. COPD, 2006, 1, 373-379.
[32]
Protein Data Bank (https://www.rcsb.org/) accession codes 1XMU and 1XOQ.

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