Molecular Docking and ADMET Profiling of Novel Isoxazole-Based Compounds for Cancer Therapy

Abstract

Since isoxazole derivatives have a variety of pharmacological actions, such as antibacterial, anticancer, and anti-inflammatory qualities, they are frequently investigated in drug discovery. We created and assessed new isoxazole derivatives in this work based on their molecular interactions with a chosen therapeutic target and pharmacokinetic characteristics. To use computational methods to evaluate novel isoxazole derivatives' drug-likeness, binding affinity, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics.

Keywords

Introduction

Figure no 1: Mechanism of cancer formation

Figure no 2: Mechanism of action of anticancer drug.

Table no1: 2D structure of derived compounds.

Compound	STRUCTURE	Compound	STRUCTURE
1		2
3		4
5		6
7		8
9		10

Table no 2: ADME Parameters of standard drug.

Standard Erlotinib	M.F.	M.W.	nHBA	nHBD	Log (ilogp)	TPSA	Rule of Five
Accepted values	----------------	<500 g/mol	<5	<10	<5	<110	Max 4
1	C22H23N3O4	393.4	6	1	3.67	74.43	4

Table no 3: ADME Parameters of derived compounds.

Compounds	M.F.	M.W.	nHBA	nHBD	Log P (ilogp)	TPSA	Rule Of Five
Accepted values	----------------	<500 g/mol	<5	<10	<5	<110	Max 4
1	C13H9N3O3	255.23	4	1	1.67	87.64	4
2	C13H14N2O	214.26	2	1	2.31	41.82	4
3	C14H9F3N2O	278.23	5	1	2.3	41.82	4
4	C15H14N2O3	270.28	4	2	2.45	71.28	4
5	C16H10F3NO4	337.25	8	2	2.63	75.72	3
6	C14H9F3N2O2	294.23	6	1	2.61	51.05	3
7	C14H12N2O	224.26	2	1	2.29	41.82	4
8	C14H9N3O	235.24	3	1	2.01	65.61	4
9	C14H12N2OS	256.31	2	1	2.44	67.12	4
10	C14H12N2O	224.26	2	1	2.16	41.82	4

      

 

 

Figure no 3: 2D,3D, structure of erlotinib, drug likeness profile.

     

Figure no 4: 2D,3D structures of new molecule.

Figure no 5:  Protein chain (2a0c), Ramachandran plot.

Table no 4:2D,3D docking results of standard drug.

Standard Compound	2D	3D
Erlotinib

Table no 5: 2D,3Ddocking results of derived compounds.

Compound	2D	3D
1
2
3
4
5
6
7
8
9
10

DISCUSSION:

The molecular docking analysis indicated that several of the newly designed compounds exhibited stronger binding affinities than Erlotinib. Compound 6 emerged as the most promising candidate, with the lowest binding energy of –9.1 kcal/mol, forming a hydrogen bond with LEU83, a residue recurrently involved in ligand interactions. This suggests a favorable binding orientation and potentially enhanced inhibitory efficiency. Similarly, Compounds 3 (–8.4 kcal/mol), 9 (–8.5 kcal/mol), and 8 (–8.0 kcal/mol) also demonstrated high binding affinities, forming multiple hydrogen bonds with essential residues such as GLU12, ASP86, and ASP145. These interactions likely enhance the compounds' stability within the ATP-binding pocket, improving their binding specificity of particular interest, Compound 9 formed four hydrogen bonds with ASP86, LYS89, and ASP145, indicating a highly stable interaction network within the active site. This extensive bonding may explain its strong binding affinity and potential bioactivity. Overall, residues including GLU12, LEU83, ASP86, and ASP145 were frequently involved in binding with top-performing compounds, suggesting their critical role in anticancer activity. In contrast, Compound 10 showed the weakest binding among the test compounds, with a binding energy of –6.4 kcal/mol, only slightly better than Erlotinib, indicating limited binding potential.

CONCLUSION:

Novel isoxazole derivatives were subjected to molecular docking investigations and in silico ADMET prediction, which demonstrated significant binding affinity for the target protein and promising drug-like characteristics. Good absorption, low toxicity, and sustained interactions within the binding site were among the drugs' positive pharmacokinetic characteristics. These results imply that the isoxazole derivatives under study have the potential to serve as lead molecules for additional medication development. To confirm their pharmacological efficacy and safety, more experimental research is necessary. To move these molecules closer to therapeutic uses, it will be crucial to combine computational and experimental methods. All the molecules demonstrate favourable results relative to the standard drug. The preceding information indicates that all drugs have affinity for the protease receptor, which is crucial in the pathophysiology of cancer. As a result, we can proceed with IN-VIVO and IN-VITRO investigations.

REFERENCES

1. Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E (September). "NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription". Genes & Development2000:14(18);2283–97.
2. Tripathi, Y. B., Tripathi, P. & Arjmandi, B. H. Nutraceuticals and cancer management. Front. Biosci. 10, 1607–1618 (2005).
3. Morris GM, Lim-Wilby M. Molecular Docking. In humana; 2008. p. 365–82.
4. Venhorst, J. et al. Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationaliza tion of experimental ligand-binding specificities. J. Med. Chem. 46(1), 74–86 (2003).
5. Kuntz, I.D. , Blaney, J.M. , Oatley, S.J. , Langridge, R. and Ferrin, T.E. (1982) A geometric approach to macromolecule-ligand interactions. J. Mol. Biol., 161 , 269–288.
6. Caruso JA, Duong MT, Carey JP, Hunt KK, Keyomarsi K. "Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies". Cancer Research. 2018;78(19);5481–5491.
7. Samtsevich AI, Nikolaienko TY, Sukhodub LF, Bulavin LA. Interaction of DNA nucleotide bases with anticancer drug ThioTEPA: molecular docking and quantum-mechanical analysis. The Ukrainian Biochemical Journal. 2014 Apr 27;86(2):50–9.
8. Murail, S. , de Vries, S.J. , Rey, J. , Moroy, G. and Tufféry, P. (2021) SeamDock: an interactive and collaborative online docking resource to assist small compound molecular docking. Front. Mol. Biosci., 8 , 716466.
9. Muhammed MT, Aki-Yalcin E. Molecular docking: Principles, advances, and its applications in drug discovery. Lett Drug Des Discov. 2024;21(3):480-95.
10. Rodrigues J, Hullatti K, Jalalpure S, Khanal P. In-vitro Cytotoxicity and in silico Molecular Docking of Alkaloids from Tiliacora acuminate. Indian Journal of Pharmaceutical Education and Research2020; 54(2); 5295 5300.
11. Kitchen, D. B., Decornez, H., Furr, J. R. & Bajorath, J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Natl. Rev. Drug Discov. 3(11), 935–949 (2004).
12. Sharma V, Alavi A. Role of Docking in Anticancer Drug Discovery. Letters in Drug Design & Discovery. 2023 Oct 1;20(10):1490–511.
13. Asiamah I, Obiri SA, Tamekloe W, Armah FA, Borquaye LS. Applications of molecular docking in natural products-based drug discovery. Sci Afr. 2023;20:e01593.
14. P SA, G HS, M CH, S MS. Insilico Molecular Docking - A tool to understand the action of Rasaushadhis. Journal of Ayurveda and Integrated Medical Sciences (JAIMS). 2017 Aug 28;2(4).
15. Bortolato A, Fanton M, Mason JS, Moro S. Molecular Docking Methodologies. In humana; 2012. p. 339–60.
16. Dias R, De Azevedo Jr W. Molecular Docking Algorithms. Current Drug Targets. 2008 Dec 1;9(12):1040–7.
17. Guedes IA, De Magalhães CS, Dardenne LE. Receptor-ligand molecular docking. Biophysical Reviews. 2013 Dec 21;6(1):75–87.
18. Dnyandev KM, Babasaheb GV, Chandrashekhar KV, Chandrakant MA, Vasant OK. A Review on Molecular Docking. International Research Journal of Pure and Applied Chemistry. 2021 May 20;60–8.
19. Sharma MK, Kumawat MK, Kumar N. MOLECULAR DOCKING STUDY OF SELECTED PHYTOCHEMICALS WITH COVID-19 MAIN PROTEASE. UTTAR PRADESH JOURNAL OF ZOOLOGY. 2021 Dec 30;1265–85.
20. Pawar S, Rohane SH, Redasani VK, Pujari S, Gadade P, Kakade S, et al. Molecular Docking using different Tools. Asian Journal of Pharmaceutical Research. 2023 Nov 22;292–6.
21. Meng, X. Y., Zhang, H. X., Mezei, M. & Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Comput. Aided Drug Des. 7, 146–157 (2011).