Design,synthesis, and enzymatic characterization of quinazoline-based CYP1A2 inhibitors |
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| Affiliation: | 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;2. School of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, China;3. Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Department of Chemistry, Dr. Babasaheb Ambedkar, Marathwada University, Aurangabad 431 004, Maharashtra, India;2. Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, India;3. Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education & Research, Shirpur 425 405, Maharashtra, India;4. Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431 401, Maharashtra, India;5. Department of Animal Biology, University of Hyderabad, Hyderabad 500 046, India;1. Faculty of Chemical Engineering, Ho Chi Minh City University of Technology (HCMUT) 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Vietnam;2. Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam;3. University of Science and Technology of Ha Noi, Viet Nam Academy of Science and Technology, 18 Hoang Quoc Viet, Ha Noi, Vietnam |
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| Abstract: | Cytochrome P450 isozyme 1A2 (CYP1A2) is one main xenobiotic metabolizing enzyme in humans. It has been associated with the bioactivation of procarcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific and potent pulmonary carcinogen. This work describes the computational design and in-silico screening of potential CYP1A2 inhibitors, their chemical synthesis, and enzymatic characterization with the ultimate aim of assessing their potential as cancer chemopreventive agents. To achieve this, a combined classifiers model was used to screen a library of quinazoline-based molecules against known CYP1A2 inhibitors, non-inhibitors, and substrates to predict which quinazoline candidates had a better probability as an inhibitor. Compounds with high probability of CYP1A2 inhibition were further computationally evaluated via Glide docking. Candidates predicted to have selectivity and high binding affinity for CYP1A2 were synthesized and assayed for their enzymatic inhibition of CYP1A2, leading to the discovery of novel and potent quinazoline-based CYP1A2 inhibitors. |
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| Keywords: | Tobacco NNK CYP1A2 Quinazoline Computational Synthesis |
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