Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review

Raju, Baddipadige; Choudhary, Shalki; Narendra, Gera; Verma, Himanshu; Silakari, Om

doi:10.1080/03602532.2021.1874406

Cited by 13 publications

(14 citation statements)

References 166 publications

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“…The LF dG Score corresponding to this standard inhibitor was found to be −6.082 kcal/mol. The reported interactions [ 26–28 ] corroborate with these results. Similarly, interactions were also analyzed for 21 designed molecules.…”

Section: Resultssupporting

confidence: 79%

“…The LF dG Score corresponding to this standard inhibitor was found to be −6.082 kcal/mol. The reported interactions [26][27][28] corroborate with these results. Similarly, interactions were also analyzed for 21 In all the designed molecules, the aromatic phenyl ring and 2benzoxazolinone were found to orient in such a way that their aromatic pi-electronic cloud is in close proximity to the aromatic cloud of the phenyl ring in Phe 171, Phe 466, and indole ring of Trp 178 to form pi-pi stacking interactions.…”

Section: Molecular Dockingsupporting

confidence: 82%

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3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Verma

Narendra

Raju

et al. 2022

Archiv der Pharmazie

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Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)‐approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations 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(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D‐quantitative structure activity relationship (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 most selective indole‐2,3‐diones‐based compound, that is, cmp 3, was further considered for scaffold hopping. Two top‐ranked bioisosteres, that is, benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one, were selected for designing new inhibitors by considering the field pattern of 3D‐QSAR. All designed molecules were mapped perfectly on the 3D‐QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5–6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D‐QSAR result. The top five inhibitor‐ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02–0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

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Section: Resultssupporting

confidence: 79%

Section: Molecular Dockingsupporting

confidence: 82%

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Verma

Narendra

Raju

et al. 2022

Archiv der Pharmazie

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“…4,5 CYP1B1 is a heme-containing monooxygenase, involved in the NADPHdependent phase I metabolism of a wide range of endogenous and exogenous compounds including some clinically approved anti-cancer drugs. 6,7 CYP1B1 was found to be the most intriguing target for most researchers due to the following reasons, (1) tissuespecific overexpression of CYP1B1 was primarily found in extrahepatic tissues such as ovarian, lung, brain, breast, and colon cancer tissues, while no detectable amount of CYP1B1 was found in adjacent normal tissues. [8][9][10] (2) It confers drug resistance by rapidly bio-transforming some anticancer drugs such as docetaxel, paclitaxel, tamoxifen, imatinib, and cisplatin.…”

Section: Introductionmentioning

confidence: 99%

Identification of potential benzoxazolinones as CYP1B1 inhibitors via molecular docking, dynamics, waterswap, and in vitro analysis

et al. 2023

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“…About 60–90% of its administered dose gets metabolized in liver and extrahepatic tissues, while 10–20% get excreted unchanged in urine; thus, only a small amount of 5-FU remains to exert its anticancer activity by inhibiting TS. In addition to this, 5-FU has to withstand one more challenge, i.e., the metabolism of 5-FU to inactive metabolite due to DPD overexpression in tumor tissues before cytotoxic nucleotides can be formed. , This type of inactivation belongs to one of the pharmacokinetic resistance mechanisms . DPD catalyzes the first step of pyrimidine degradation, i.e., nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of thymine and uracil moieties of drug molecules.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to this, 5-FU has to withstand one more challenge, i.e., the metabolism of 5-FU to inactive metabolite due to DPD overexpression in tumor tissues before cytotoxic nucleotides can be formed. 6,7 This type of inactivation belongs to one of the pharmacokinetic resistance mechanisms. 8 DPD catalyzes the first step of pyrimidine degradation, i.e., nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of thymine and uracil moieties of drug molecules.…”

Section: ■ Introductionmentioning

confidence: 99%

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Verma

Narendra

Raju

et al. 2022

ACS Pharmacol. Transl. Sci.

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5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutics for the treatment of cancers associated with the aerodigestive tract, breast, and colorectal system. The efficacy of 5-FU is majorly affected by dihydropyrimidine dehydrogenase (DPD) as it degrades more than 80% of administered 5-FU into an inactive metabolite, dihydrofluorouracil. Herein we discuss the molecular mechanism of this inactivation by analyzing the interaction pattern and electrostatic complementarity of the DPD–5-FU complex. The basis of DPD overexpression in cancer cell lines due to significantly distinct levels of the miRNAs (miR-134, miR-27b, and miR-27a) compared to normal cells has also been outlined. Additionally, some kinases including sphingosine kinase 2 (SphK2) have been reported to correlate with DPD expression. Currently, to address this problem various strategies are reported in the literature, including 5-FU analogues (bypass the DPD-mediated inactivation), DPD downregulators (regulate the DPD expression levels in tumors), inhibitors (as promising adjuvants), and formulation development loaded with 5-FU (liposomes, nanoparticles, nanogels, etc.), which are briefly discussed in this Review.

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Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review

Cited by 13 publications

References 166 publications

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Identification of potential benzoxazolinones as CYP1B1 inhibitors via molecular docking, dynamics, waterswap, and in vitro analysis

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

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