3D-QSAR and scaffold hopping based designing of some novel selective aldehyde dehydrogenase 1A1 inhibitors: synthesis and biological evaluation Himanshu Verma 1 , Gera Narendra 1 , Baddipadige Raju 1 , Manoj Kumar 1 , Subheet K. Jain 2 , Gurleen K. Tung 2 , Pankaj K. Singh 3 , Prof. Om Silakari 1 1 Punjabi University, India, 2 Guru Nanak Dev University, India, 3 University of Turku, Finland Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is over expressed in various types of cancer cell lines and is the major cause of resistance to the FDA-approved drug "Cyclophosphamide" (CP). In cancer condition, CP undergoes a sequence of biotransformation to form an active metabolite "Aldophosphamide” which further biotransforms to its putative cytotoxic metabolite “phosphoramide mustard”. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite carboxyphosphamide via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of Benzo[ d ] oxazol-2(3 H )-one and 2-Oxazolo[4,5- b ]pyridin-2(3 H )-one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using validated 3D-QSAR model coupled with scaffold hopping. The 3D-QSAR model was developed using reported indole-2,3-diones based ALDH1A1 inhibitors which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The highest selective indole-2,3-diones based compound i.e. Cmp.3 was further considered for carrying scaffold hopping. Two top ranked bioisosteres i.e. Benzo[ d ]oxazol-2(3 H )-one and 2-Oxazolo[4,5- b ]pyridin-2(3 H )-one were selected for designing new inhibitors by considering the field pattern of 3D-QSAR. All designed molecules were mapped perfectly on 3D-QSAR model and found to be predictive with good inhibitory potency pIC 50 ranges from 7.5-6.8. Further molecular docking was carried out for each designed molecule to identify key interactions which are required for ALDH1A1 inhibition and to authenticate 3D-QSAR result. The top five inhibitors-ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In-vitro enzyme assay of 21 compounds suggested that these compounds are selective towards ALDH1A1 over other two isoforms i.e. ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times selective towards ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed IC 50 value in the range of 0.02- 0.80mM which indicates potential of these to be developed as an adjuvant therapy for CP resistance. References 1. Verma, H., Narendra, G., Raju, B., Kumar, M., Jain, S.K., Tung, G.K., Singh, P.K. and Silakari, O., 2022. 3D-QSAR and scaffold hopping based designing of benzo[d]oxazol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2 (3H)-one derivatives as selective ALDH1A1 inhibitors.Archiv der Pharmazie.
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