In silico study of 2,4,5-trisubstituted thiazoles as inhibitors of tuberculosis using 3D-QSAR, molecular docking, and ADMET analysis

Yıl 2022, Cilt: 9 Sayı: 2, 452 - 468, 31.05.2022

Ayoub Khaldan , Soukaina Bouamrane , Reda El-mernissi , Hamid Maghat , Mohammed Aziz Ajana , Abdelouahid Sbai , Mohammed Bouachrıne , Tahar Lakhlıfı

https://doi.org/10.31202/ecjse.961940

Öz

In order to discover new efficient drug used as inhibitor of tuberculosis, three-dimensional quantitative structure-activity relationship (3D-QSAR) was executed on set of eighteen 2,4,5-trisubstituted thiazoles compounds. CoMFA and CoMSIA models were molded using 14 molecules as training set. They give a significant coefficient of R2 (0.995 and 0.982 respectively) and important values of Q2 (0.533 and 0.601, respectively). The robust of these models was checked by an external validation using a test set of 4 molecules, affords significant R2test values of 0.654 and 0.648 for CoMFA and CoMSIA models, respectively. CoMFA and CoMSIA contour maps provided much valuable information to identify the main regions impacting (decreasing or increasing) the antituberculosis activity. These outcomes guided us to design new entities with important activities. Molecular docking was put into effect to guess the types and modes of interactions between 2,4,5-trisubstituted thiazoles molecules and receptor (PDB: 4ZDJ). In silico ADMET analysis was executed to measure the pharmacokinetic properties of newly designed molecules.

Anahtar Kelimeler

Molecular docking, 3D-QSAR, anti-tuberculosis, thiazoles, ADMET

Kaynakça

• [1]. Li, Q., Lu, X., New antituberculosis drugs targeting the respiratory chain, Chinese Chemical Letters, 2020, 31: 1357- 1365.
• [2]. Global tuberculosis report 2020. Geneva: World Health Organization, 2020. https://apps.who.int/iris/handle/10665/336069 (accessed 173 October 2020).
• [3]. Fontecave, M., Ollagnier-de-Choudens, S., Mulliez, E., Biological Radical Sulfur Insertion Reactions, Chemical Reviews, 2003, 103(6): 2149- 2166.
• [4]. (a) Cascioferro, S., Parrino, B., Carbone, D., Schillaci, D., Giovannetti, E., Cirrincione, G., Diana, P., Thiazoles, their benzofused systems, and thiazolidinone derivatives: Versatile and promising tools to combat antibiotic resistance, Journal of Medicinal Chemistry , 2020, 63 (15): 7923-7956. (b) Beno, B.R., Yeung, K., Bartberger, M.D., Pennington, L.D., Meanwell, N.A., A Survey of the role of noncovalent sulfur interactions in drug design, Journal of Medicinal Chemistry, 2015, 58: 4383−4438.
• [5]. Khaldan, A., Bouamrane, S., El-mernissi, R., Maghat, H., Ajana, M.A., Sbai, A., Bouachrine, M., Lakhlifi T., 3D-QSAR modeling, molecular docking and ADMET properties of benzothiazole derivatives as a-glucosidase inhibitors, Materials Today: Proceedings, 2021, 45: 7643- 7652.
• [6]. Cramer, R.D., Patterson, D.E., Bunce, J.D., Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins, Journal of the American Chemical Society, 1988, 110(18): 5959–5967.
• [7]. Klebe, G., Abraham, U., Mietzner, T., Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity, Journal of Medicinal Chemistry, 1994, 37(24): 4130–4146.
• [8]. Karale, U.B., Krishna, V.S., Krishna, E.V., Choudhari, A.S, Shukla, M., Gaikwad, V.R., Mahizhaveni, B., Chopra, S., Misra, S., Sarkar, D., Sriram, D., Dusthackeer, V.N.A., Rode, H.B., Synthesis and biological evaluation of 2,4,5-trisubstituted thiazoles as antituberculosis agents effective against drug-resistant tuberculosis, European Journal of Medicinal Chemistry, 2019, 178: 315- 328.
• [9]. Sybyl 8.1; Tripos Inc.: St. Louis, MO, USA, 2008; Available online: http://www.tripos.com (accessed on 26 January 2011).
• [10]. Clark, M., Cramer, R.D., Van Opdenbosch, N., Validation of the general purpose tripos 5.2 force field, Journal of Computational Chemistry, 1989, 10: 982–1012.
• [11]. Purcell, W.P., Singer, J.A., A brief review and table of semiempirical parameters used in the Hueckel molecular orbital method, Journal of Chemical & Engineering Data, 1967, 12: 235–246.
• [12]. Ståhle, L., Wold, S., Multivariate data analysis and experimental design in biomedical research, Progress in Medicinal Chemistry, 1988, 25: 291–338.
• [13]. Zheng, J., Xiao, G., Guo, J., Zheng, Y., Gao, H., Zhao, S, Zhang, K., Sun, P., Exploring QSARs for 5-lipoxygenase (5-LO) inhibitory activity of 2-substituted 5-hydroxyindole-3-carboxylates by CoMFA and CoMSIA, Chemical Biology & Drug Design, 2011, 78(2):314-321.
• [14]. Wold, S., Validation of QSAR’s, Quantitative Structure-Activity Relationships, 1991, 10(3): 191–193.
• [15]. Rücker, C., Rücker, G., Meringer, M., y-Randomization and its variants in QSPR/ QSAR, Journal of Chemical Information and Modeling, 2007, 47(6): 2345–2357.
• [16]. Mori, G., Chiarelli, L.R., Esposito, M., et al, Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG, Chemical Biology, 2015, 22(7):917-27.
• [17]. Dassault Syst emes BIOVIA, Discovery Studio Modeling Environment, Release 2017, Dassault Syst emes, San Diego, 2016 [WWW document], http://accelrys.com/products/collaborativescience/biovia-discovery-studio/. (Accessed 25 February 2017).
• [18]. W. DeLanoW., The PyMOL Molecular Graphics System DeLano Scientific, Palo Alto, CA, USA, 2002. http://www.pymol.org. (Accessed 25 February 2017).
• [19]. Pires, D.E.V., Blundell, T.L., Ascher, D.B., pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures, Journal of Medicinal Chemistry, 2015, 58 (9): 4066–4072.
• [20]. Daina, A., Michielin, O., Zoete, V., SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Scientific Reports, 2017, 7: 42717.
• [21]. Veber, D.F., Johnson, S.R., Cheng, H-Y., Smith, B.R., Ward, K.W., Kopple, K.D., Molecular properties that influence the oral bioavailability of drug candidates, Journal of Medicinal Chemistry, 2002, 45(12): 2615–2623.
• [22]. Upadhyay, R.K., Drug delivery systems, CNS protection, and the blood brain barrier, BioMed Research International, 2014 (2014): 869269.