QSAR and docking studies of 3, 5-dimethylpyrazole as potent inhibitors of Phosphodiesterase-4
Abstract
A quantitative structure-activity relationship (QSAR) study was performed to develop a model on a series of 3, 5-dimethylpyrazole containing furan moiety derivatives which exhibited considerable inhibitory activity against PDE4B. The obtained model has correlation coefficient (r) of 0.934, squared correlation coefficient (r2) of 0.872, and leave-one-out (LOO) cross-validation coefficient (Q2) value of 0.733. The predictive power of the developed model was confirmed by the external validation which has (r2) value of 0.812. These parameters confirm the stability and robustness of the model to predict the activity of a new designed set of 3,5-dimethyl-pyrazole derivatives (I-XV), results indicated that the compound III, V, XIII, and XV showed the strongest inhibition activity (IC50 = 0.2813, 0.5814, 0.6929, 0.6125μM, respectively) against PDE4B compared to the reference rolipram with (IC50=1.9μM). Molecular docking was performed on a new designed compound with PDE4B protein (3o0j). Docking results showed that compounds (X and IX) have high docking affinity of -36.2037 and -33.2888 kcal/mol respectively.
Keywords: QSAR, molecular docking, pyrazole derivatives, PDE4 inhibitors, anti-inflammatory.
Keywords:
QSAR, molecular docking, pyrazole derivatives, PDE4 inhibitors, anti-inflammatory
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References
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[2]. Chiricozzi A, Caposiena D, Garofalo V, Cannizzaro MV, Chimenti S, Saraceno R. A new therapeutic for the treatment of moderate to severe plaque psoriasis: apremilast. Expert review of clinical immunology. 2016; 12(3):237-249.
[3]. Ahmed F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V. Cyclic nucleotide phosphodiesterses: important signaling modulators and therapeutic targets. Oral diseases. 2015; 21(1):e25-e50.
[4]. Halpin DM. ABCD of the phosphodiesterase family: interaction and differential activity in COPD. International journal of chronic obstructive pulmonary disease. 2008; 3(4):543.
[5]. Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signaling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. British journal of pharmacology. 2012; 165(5):1288-1305.
[6]. Maurice DH, Ke H, Ahmed F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nature reviews drug discovery. 2014; 13(4):290-314.
[7]. Vang AG, Basole C, Dong H, Nguyen RK, Housley W, Guernsey L, Adami AJ, Thrall RS, Clark RB, Epstein PM, Brocke S. Differential expression and function of PDE8 and PDE4 in effector T cells: implications for PDE8 as a drug target in inflammation. Frontier in pharmacology. 2016; 7:259.
[8]. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 2007; 76:481-511.
[9]. Omori K, Kotera J. Overview of PDEs and their regulation. Circulation research. 2007; 100(3):309-327.
[10]. Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 2001; 69:249-315.
[11]. Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug discovery today.2005; 10(22):1503-1519.
[12]. Michalski JM, Golden G, Ikari J, Rennard SI. PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clinical Pharmacology and Therapeutics. 2012; 91(1):134-142.
[13]. Martinez A, Gil C. cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases. Expert opinion on therapeutic patents. 2014; 24(12):1311-1321.
[14]. Yu H, Zhong J, Niu B, Zhong Q, Xiao J, Xie J, Lin M, Zhou Z, Xu J, Wang H. Inhibition of phosphodiesterase 4 by FCPR03 alleviates chronic unpredictable mild stress-induced depressive-like behaviors and prevents dendritic spine loss in mice hippocampi. International Journal of Neuropsychopharmacology. 2019; 22(2):142-155.
[15]. Richter W, Xie M, Scheitrum C, Krall J, Movsesian MA, Conti M. Conserved expression and functions of PDE4 in rodent and human heart. Basic research in cardiology. 2011; 106:249-262.
[16]. Wittmann M, Helliwell PS. Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatology and theraby. 2013; 3(1):1-15.
[17]. Singh D, Beeh KM, Colgan B, Kornmann O, Leaker B, Watz H, Lucci G, Geraci S, Emirova A, Govoni M, Nandeuil MA. Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD. Respiratory research. 2019; 20(1):180.
[18]. Brown WM. Treating COPD with PDE4 inhibitors. International journal of chronic obstructive pulmonary disease. 2007; 2(4):517-533.
[19].Halder AK, Moura AS, Cordeiro MND. QSAR modeling: a therapeutic patent review 2010-present. Expert opinion on therapeutic patents. 2018; 28(6):467-476.
[20]. Tropsha A. Best practices for QSAR model development, validation, and exploitation. Molecular informatics. 2010; 29(6-7):476-488.
[21]. Lima AN, Philot EA, Trossini GHG, Scott LPB, Maltarollo VG, Honorio KM. Use of machine learning approaches for novel drug discovery. Expert opinion on drug discovery. 2016; 11(3):225-239.
[22]. Hu DK, Zhao DS, He M, Jin HW, Tang YM, Zhang LH, Song GP, Cui ZN. Synthesis and bioactivity of 3, 5-dimethylpyrazole derivatives as potential PDE4 inhibitors. Bioorganic and medicinal chemistry letters. 2018; 28(19):3276-3280
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1.
Mahgoub Mohamed H, Mohammed Hussien ABW, Mohammed Saeed A. QSAR and docking studies of 3, 5-dimethylpyrazole as potent inhibitors of Phosphodiesterase-4. JDDT [Internet]. 15Feb.2021 [cited 4Mar.2021];11(1-s):86-3. Available from: http://jddtonline.info/index.php/jddt/article/view/4718
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