Author(s): Minhajul Arfeen, Ruba Alqasem, Mashal Alwahabi


DOI: 10.52711/0974-360X.2024.00255   

Address: Minhajul Arfeen*, Ruba Alqasem, Mashal Alwahabi
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah, 51452, Saudi Arabia.
*Corresponding Author

Published In:   Volume - 17,      Issue - 4,     Year - 2024

Two series of novel compounds were designed by combining indomethacin and ibuprofen with sixteen sulfa drugs. These compounds were systematically evaluated through target fishing using the Pharm Mapper, leading to the identification of DPP-4, AChE, and COX-2 as potential targets. Molecular docking was performed to evaluate the binding affinity of designed compounds against the identified three target proteins. The results revealed that the designed compounds exhibited binding affinities ranging from ~8 to -12kcal/mol, 12 to 13 kcal/mol and 8 to 11kcal/mol for DPP-4, AChE and COX-2 respectively. The binding affinities were found to be comparable or higher than binding affinity of co-crystallized ligand, which was found to be ~10, 12 and 9 kcal/mol respectively. Further investigation into the binding modes of these compounds was carried out. Notably, for DPP-4 complexes, interactions with Arg125, Glu205, and Glu206 were observed which are essential for substrate and inhibitor binding. For AChE complexes, interactions involved crucial His447 residues, essential for acetylcholine hydrolysis. In the case of COX-2, hydrogen bond interaction was noted with Arg120 located at the entrance of the hydrophobic channel. Despite favorable binding potentials, ADME profiling highlighted five compounds (1A, 1F, 1G, 1H, and 1O) with drug-like characteristics but lacking blood-brain barrier permeation ability. Out of five compounds, 1H stood out, demonstrating superior binding affinity and interactions vital residues necessary for catalytic activity of three enzymes. Thus, 1H emerges as a promising candidate for Multi-Targeted Drug-Like (MTDL) development aimed at addressing diabetes mellitus related dementia.

Cite this article:
Minhajul Arfeen, Ruba Alqasem, Mashal Alwahabi. Multi Targeted Ligands for Potential Inhibition of Dipeptidyl Peptidase 4, Acetylcholinesterase and Cyclooxygenase 2. Research Journal of Pharmacy and Technology.2024; 17(4):1611-0. doi: 10.52711/0974-360X.2024.00255

Minhajul Arfeen, Ruba Alqasem, Mashal Alwahabi. Multi Targeted Ligands for Potential Inhibition of Dipeptidyl Peptidase 4, Acetylcholinesterase and Cyclooxygenase 2. Research Journal of Pharmacy and Technology.2024; 17(4):1611-0. doi: 10.52711/0974-360X.2024.00255   Available on:

1.    Mani V, Arfeen M, Mohammed HA, et al. Sukkari dates seed improves type-2 diabetes mellitus-induced memory impairment by reducing blood glucose levels and enhancing brain cholinergic transmission: In vivo and molecular modeling studies. Saudi Pharm J. 2022; 30(6): 750-763. doi:
2.    Cholerton B, Baker LD, Montine TJ, Craft S. Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach. Diabetes Spectr. 2016; 29(4): 210-219. doi:10.2337/ds16-0041
3.    Srivastava A, Mishra A, Rai AK. Synthesis, characterization and evaluation of ulcerogenic potential for NSAIDs-alendronate based prodrug. Res J Pharm Technol. 2020; 13(5): 2107-2111. doi:10.5958/0974-360X.2020.00379.0
4.    Srivastava A, Mishra A, Rai AK. Nsaids-alendronate based prodrug for bone specific drug targeting. Res J Pharm Technol. 2020; 13(7): 3520-3523. doi:10.5958/0974-360X.2020.00623.X
5.    Akgul O, Di Cesare Mannelli L, Vullo D, et al. Discovery of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs–CAIs) for the Management of Rheumatoid Arthritis. J Med Chem. 2018;61(11):4961-4977. doi:10.1021/acs.jmedchem.8b00420
6.    Lucarini L, Durante M, Sgambellone S, et al. Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis. Biomolecules. 2020; 10(9): 1307.
7.    Markowicz-Piasecka M, Sadkowska A, Sikora J, Broncel M, Huttunen KM. Novel sulfonamide-based analogs of metformin exert promising anti-coagulant effects without compromising glucose-lowering activity. Pharmaceuticals. 2020; 13(10): 1-28. doi:10.3390/ph13100323
8.    Sharma P, Dayma V, Dwivedi A, et al. Synthesis of sulpha drug based hydroxytriazene derivatives: Anti-diabetic, antioxidant, anti-inflammatory activity and their molecular docking studies. Bioorg Chem. 2020;96:103642. doi:
9.    Prafulla S, Lata P, Priya R, Vidya S. Novel Curcumin Derivatives: Targeted for Anti-Inflammatory Activity. Asian J Res Chem. 2019; 12(2): 49. doi:10.5958/0974-4150.2019.00011.7
10.    Vijaya Nagini D, Krishna MSR, Karthikeyan S. Identification of novel dipeptidyl peptidase-iv inhibitors from ferula asafoetida through gc-ms and molecular docking studies. Res J Pharm Technol. 2020; 13(11): 5072-5076. doi:10.5958/0974-360X.2020.00888.4
11.    Lakshmi Kanthamma S, Kriszhnamurthi J, Hemalatha CN, Vijey Aanandhi M. Insilico approach of interaction studies in Bacopa monnieri compounds targeting multi-proteins for Alzheimer’s disease. Res J Pharm Technol. 2018; 11(4): 1522-1526. doi:10.5958/0974-360X.2018.00283.4
12.    Sravani M, Sai Lakshmi P, Amuktha Reddy K, Naga Deepthi N, Kantheti USK. Insilico analysis and docking of tacrine and donepezil derivatives targeting histamine-N-methyltransferase and acetyl cholinesterase protein respectively for Alzheimer’s disease. Res J Pharm Technol. 2013; 6(1): 86-89.
13.    Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455-461.
14.    Satpute UM, Rohane SH. Efficiency of AUTODOCK: Insilico study of Pharmaceutical Drug Molecules. Asian J Res Chem. 2021;14(1):1-5. doi:10.5958/0974-4150.2021.00016.x
15.    Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16): 2785-2791.
16.    Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7(1): 42717. doi:10.1038/srep42717
17.    Nojima H, Kanou K, Terashi G, et al. Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor. BMC Struct Biol. 2016; 16(1): 1-14. doi:10.1186/s12900-016-0062-8
18.    Bajda M, Wiȩckowska A, Hebda M, Guzior N, Sotriffer CA, Malawska B. Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci. 2013; 14(3): 5608-5632. doi:10.3390/ijms14035608
19.    Macdonald IR, Martin E, Rosenberry TL, Darvesh S. Probing the Peripheral Site of Human Butyrylcholinesterase. Biochemistry. 2012; 51(36): 7046-7053. doi:10.1021/bi300955k
20.    Kiefer JR, Pawiitz JL, Moreland KT, et al. Structural insights into the stereochemistry of the cyclooxygenase reaction. Nature. 2000; 405(6782): 97-101. doi:10.1038/35011103
21.    Tabatabaie T, Waldon AM, Jacob JM, Floyd RA, Kotake Y. COX-2 Inhibition Prevents Insulin-Dependent Diabetes in Low-Dose Streptozotocin-Treated Mice. Biochem Biophys Res Commun. 2000; 273(2): 699-704. doi:
22.    Roppongi S, Suzuki Y, Tateoka C, et al. Crystal structures of a bacterial dipeptidyl peptidase IV reveal a novel substrate recognition mechanism distinct from that of mammalian orthologues. Sci Rep. 2018; 8(1): 1-5. doi:10.1038/s41598-018-21056-y
23.    Rodhi AM, Yap PG, Abayomi OO, Gan CY. A review on the types of amino acid at ultimate, penultimate and antepenultimate position in some dipeptidyl-peptidase IV inhibitory peptides based on molecular docking analysis. Food Chem Adv. 2023; 2(October). doi:10.1016/j.focha.2023.100244
24.    Macalalad MAB, Gonzales AA. In Silico Screening and Identification of Antidiabetic Inhibitors Sourced from Phytochemicals of Philippine Plants against Four Protein Targets of Diabetes (PTP1B, DPP-4, SGLT-2, and FBPase). Molecules. 2023; 28(14): 1-33. doi:10.3390/molecules28145301
25.    Mathur V, Alam O, Siddiqui N, et al. Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents. Molecules. 2023; 28(15). doi:10.3390/molecules28155860
26.    Zhang Y, Kua J, McCammon JA. Role of the Catalytic Triad and Oxyanion Hole in Acetylcholinesterase Catalysis:  An ab initio QM/MM Study. J Am Chem Soc. 2002; 124(35): 10572-10577. doi:10.1021/ja020243m
27.    Mani V, Arfeen M, Rabbani SI, Shariq A, Amirthalingam P. Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study. Molecules. 2022; 27(21). doi:10.3390/molecules27217364
28.    Lu SH, Wu JW, Liu HL, et al. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies. J Biomed Sci. 2011; 18(1): 8. doi:10.1186/1423-0127-18-8
29.    Peitzika SC, Pontiki E. A Review on Recent Approaches on Molecular Docking Studies of Novel Compounds Targeting Acetylcholinesterase in Alzheimer Disease. Molecules. 2023; 28(3). doi:10.3390/molecules28031084
30.    Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG. Investigating Substrate Promiscuity in Cyclooxygenase-2: The role of ARG-120 and residues lining the hydrophobic groove. J Biol Chem. 2012; 287(29): 24619-24630. doi:
31.    Vecchio AJ, Orlando BJ, Nandagiri R, Malkowski MG. Investigating substrate promiscuity in cyclooxygenase-2 the role of Arg-120 and residues lining the hydrophobic groove. J Biol Chem. 2012; 287(29): 24619-24630. doi:10.1074/jbc.M112.372243
32.    Blobaum AL, Xu S, Rowlinson SW, et al. Action at a distance: Mutations of peripheral residues transform rapid reversible inhibitors to slow, tight binders of cyclooxygenase-2. J Biol Chem. 2015; 290(20): 12793-12803. doi:10.1074/jbc.M114.635987

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available