ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

3D-QSAR, drug-likeness, ADMET prediction, and molecular docking studies in silico of novel 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline derivatives as MALT1 protease inhibitors for the treatment of B cell lymphoma

Rachid Haloui, Ossama Daoui, Khaoula Mkhayar, Mohamed El Yaqoubi, Souad Elkhattabi, Amal Haoudi, Youssef Kandri Rodi, Fouad Chahdi Ouazzani, and Samir Chtita

Laboratory of Engineering, Systems and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, Fez, Morocco

E-mail: rachid.haloui@usmba.ac.ma

Received: 17 August 2022  Accepted: 8 December 2022

Abstract:

In the present paper, a set of 42 derivatives for 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline are investigated in silico combining 3D-QSAR study, drug-likeness, ADMET properties, and molecular docking. The study is carried out to elaborate the reliable 3D-QSAR models using the CoMFA and CoMSIA techniques. CoMFA (Q² = 0.637, R² = 0.978, SEE = 0.058) and CoMSIA (Q² = 0.544, R² = 0.949, SEE = 0.091) models show the two elaborated models have been reliable and statistically significant. The reliability of the obtained models was validated using validation methods such as internal, external, and Y-randomization validation. Based on the contour maps of the CoMFA and CoMSIA models, we obtained information that allows us to propose five new molecules with higher MALT1 inhibitory activity than the 40 compounds. The five compounds were then examined for their drug-like and ADMET properties. Based on the results, two compounds T1 and T2 have very good ADMET properties. The two molecules selected by their ADMET properties T1 and T2 were submitted to the molecular docking test to examine the bindings established between the two newly designed molecules and the MALT1 protein. The obtained results show that the new molecules T1 and T2 have high stability in the active site of MALT1 and more efficient binding affinity compared to the reference compound 26. The two new molecules T1 and T2 may be an interesting proposition for in vitro studies in the treatment of diffuse large B cell lymphoma.

Keywords: MALT1; 3D-QSAR; Drug-likeness; ADMET; Molecular docking

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-022-02627-w

Chemical Papers 77 (4) 2255–2274 (2023)