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Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
CYP19 is a mammalian aromatase, which can be targeted to develop drugs against hormone-responsive cancers. This enzyme is capable of transformation of androgens to estrogens, and reduction of the level of estrogen is an effective way to treat cancers (Guengerich, 2002). Letrozole and anastrazole are drugs that are manufactured based on this mechanism (Brodie, 1994). CYP3A4 can be targeted for developing drugs and prophylactic agents. One example for potent drug candidate development is based on inhibiting CYP3A4 to slow down the metabolism of expensive drugs. The goal is to use lower dose of the drug and to achieve better exposure in target organs (Guengerich, 2002). CYP3A4 is also a promising target for chemotherapeutic agents, e.g., gemcitabine, cisplatin, carboplatin, docetaxel, and paclitaxel used against non-small cell lung cancer (NSCLC). In-silico drug target interaction studies revealed better combination treatment regimen for advanced NSCLC using gemcitabine and carboplatin (Chun et al., 2001; Peter Guengerich et al., 2003; Subhani and Jamil, 2015). Same principle has been applied to CYP1B1. Inhibitors are developed targeting this enzyme, to block the activation of exogenous carcinogens, including estrogens 23, 24, and 25 (Langouet et al., 1995; Chun et al., 2001; Guengerich, 2002; Peter Guengerich et al., 2003). The applications of wild-type CYPs in production of drugs and drug metabolites are summarized in Table 14.1.
Cecropia pachystachya Trécul: identification, isolation of secondary metabolites, in silico study of toxicological evaluation and interaction with the enzymes 5-LOX and α-1-antitrypsin
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Penina Sousa Mourão, Rafael de Oliveira Gomes, Clara Andrezza Crisóstomo Bezerra Costa, Orlando Francisco da Silva Moura, Herbert Gonzaga Sousa, George Roberto Lemos Martins Júnior, Danniel Cabral Leão Ferreira, Antônio Luiz Martins Maia Filho, Johnnatan Duarte de Freitas, Mahendra Rai, Francisco Das Chagas Alves Lima, Antonio Euzébio Gourlart Santana, Mariana Helena Chaves, Wellington Dos Santos Alves, Valdiléia Teixeira Uchôa
CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are important enzymes in drug interactions and belong to the cytochrome P450 enzyme family, which is a family of monooxygenases involved in drug metabolism and responsible for metabolism of xenobiotics (Braz et al. 2018; Silva, da Silva, and Holanda 2020; Silvado 2008). Inhibition of these enzymes may trigger unwanted effects such as drug accumulation and or increased toxicity of the drug affected by the interaction, or reduced effectiveness (Braz et al. 2018). The last prediction analyzed here in PreADMET results is the similarity of bioactive compounds to a drug, which can be described by Lipinski´s Rule (also known as Lipinski´s Rule 5) which establishes molecular parameters to determine if molecules display reliable potential to become a new drug (Gomes and Leite 2021).