13 results on '"Choudhary, Shalki"'
Search Results
2. Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect.
- Author
-
Narendra, Gera, Choudhary, Shalki, Raju, Baddipadige, Verma, Himanshu, and Silakari, Om
- Subjects
PHARMACOGENOMICS ,GENETIC polymorphisms ,ANTINEOPLASTIC agents ,PHARMACOKINETICS ,SINGLE nucleotide polymorphisms ,HUMAN genetics ,DIHYDROPYRIMIDINE dehydrogenase - Abstract
The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person's response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. Identification of missense SNP-mediated mutations in the regulatory sites of aldose reductase (ALR2) responsible for treatment failure in diabetic complications.
- Author
-
Vyas, Bhawna, Choudhary, Shalki, Verma, Himanshu, Kumar, Manoj, and Malik, Ashok Kumar
- Subjects
ALDOSE reductase ,MISSENSE mutation ,TREATMENT failure ,REGULATOR genes ,AMINO acid residues ,INTERNET servers - Abstract
Scientific pieces of evidence indicate that the polymorphism in the ALR2 regulatory gene favors the susceptibility to diabetic complications (DCs). Previous studies have uncovered several single nucleotide polymorphisms (SNPs) in the ALR2 regulatory sites that negatively modulate the activity of this enzyme and eventually increase the risks of DCs. In view of this, the current study aimed at investigating whether the mutation as a resultant of missense SNPs in the regulatory site of ALR2 enzyme can also hamper the interactions of ALR2 inhibitors with the key amino acid residues in the ALR2 binding site. Around 202 SNPs in the ALR2 gene were reported in the dbSNP database. Out of these, eighteen SNPs that are responsible for point mutations in the regulatory sites of ALR2 enzyme were identified and considered for the study. Identified SNPs were then categorized as stabilizing or destabilizing using various in silico tools and webservers. The resulting mutational constructs of ALR2 were further probed for their influence on the binding affinities and binding modes with well-known ALR2 inhibitors using structure-based analyses. This study identified three destabilizing SNPs, i.e., rs779176563 (C298S), rs1392886142 (G16A), and rs1407261115 (A245T), that lead to the compromised response to most of the ALR2 inhibitors which are in clinical trials. On the other hand, treatment with these ALR2 inhibitors may benefit the population which carries missense SNPs rs748119899, rs1402962430, and rs1467939858 that code for W219S, Q183V, and S214A, respectively. Overall findings of the study suggest that one SNP in the inhibitor site and two SNPs in the co-factor site of ALR2 may be responsible for the low efficacy and unsuccessful journey of ALR2 inhibitors in the clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
4. Virtual screening of epalrestat mimicking selective ALR2 inhibitors from natural product database: auto pharmacophore, ADMET prediction and molecular dynamics approach.
- Author
-
Choudhary, Shalki and Silakari, Om
- Published
- 2022
- Full Text
- View/download PDF
5. Identification of kinase inhibitors that rule out the CYP27B1-mediated activation of vitamin D: an integrated machine learning and structure-based drug designing approach.
- Author
-
Mahajan, Kanupriya, Verma, Himanshu, Choudhary, Shalki, Raju, Baddipadige, and Silakari, Om
- Abstract
CYP27B1, a cytochrome P450-containing hydroxylase enzyme, converts vitamin D precursor calcidiol (25-hydroxycholecalciferol) to its active form calcitriol (1α,25(OH)
2 D3 ). Tyrosine kinase inhibitor such as imatinib is reported to interfere with the activation of vitamin D3 by inhibiting CYP27B1 enzyme. Consequently, there is a decrease in the serum levels of active vitamin D that in turn may increase the relapse risk among the cancer patients treated with imatinib. Within this framework, the current study focuses on identifying other possible kinase inhibitors that may affect the calcitriol level in the body by inhibiting CYP27B1. To achieve this, we explored multiple machine learning approaches including support vector machine (SVM), random forest (RF), and artificial neural network (ANN) to identify possible CYP27B1 inhibitors from a pool of kinase inhibitors database. The most reliable classification model was obtained from the SVM approach with Matthews correlation coefficient of 0.82 for the external test set. This model was further employed for the virtual screening of kinase inhibitors from the binding database (DB), which tend to interfere with the CYP27B1-mediated activation of vitamin D. This screening yielded around 4646 kinase inhibitors that were further subjected to structure-based analyses using the homology model of CYP27B1, as the 3D structure of CYP27B1 complexed with heme was not available. Overall, five kinase inhibitors including two well-known drugs, i.e., AT7867 (Compound-2) and amitriptyline N-oxide (Compound-3), were found to interact with CYP27B1 in such a way that may preclude the conversion of vitamin D to its active form and hence testify the impairment of vitamin D activation pathway. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
6. Functional relationship of SNP (Ala490Thr) of an epigenetic gene EZH2 results in the progression and poor survival of ER+/tamoxifen treated breast cancer patients.
- Author
-
Gautam, Nisha, Verma, Himanshu, Choudhary, Shalki, Kaur, Satbir, and Silakari, Om
- Abstract
EZH2 is a classic histone methyltransferase that causes the trimethylation of H3K27 and consequently suppresses the cancer preventive genes. The role of elevated levels of EZH2 expression in breast cancer aggressiveness and poor prognosis is very well established. The present study focusses on the insight of the clinically important SNPs of EZH2 gene in determining the structure–function relationship towards breast cancer susceptibility. For this purpose the EZH2 SNPs (rs41277434A>C and rs201135441C>T (A490T)) were computationally explored and further the prediction outcomes were validated by performing population-based association and pharmacogenetic study in north Indian region of Punjab. The results of the present analysis provided the novel insight of rs201135441C>T (A490T) mutation, that A>T change i.e. nonpolar amino acid to polar amino acid stabilizes the enzyme-substrate (EZH2-Histone) complex which in turn promotes trimethylation over histone 3 (H3) at lysine residue 27 (H3K27me3) and this might be leading to the methylation of the promoter region of various cancer preventive genes, hence may increase the risk of breast cancer susceptibility. Further the association based study of SNP rs201135441C>T (A490T) support the in silico outcomes by revealing that the T mutant allele of rs201135441 has significantly increased the risk of breast cancer susceptibility and also reduce the overall survival and progression free survival of ER+/tamoxifen treated breast cancer patients and triple negative breast cancer (TNBC) patients, respectively. To the best of our knowledge, this is the first study on EZH2 polymorphism with breast cancer. In conclusion, these findings suggest that these variations in the EZH2 gene may have strong clinical significance as they can be targeted for prognosis, prevention and in drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
7. Pharmacophore-based designing of putative ROS-1 targeting agents for NSCLC.
- Author
-
Pathak, Disha, Choudhary, Shalki, Singh, Pankaj Kumar, Singh, Manjinder, Chadha, Navriti, and Silakari, Om
- Abstract
Non-small cell lung cancer (NSCLC) is a fatal non-immunogenic malignancy, and proto-oncogene receptor tyrosine kinase (ROS-1) is one of its clinically relevant biomarkers. In this context, herein, we report a series of benzimidazol-2-amine derivatives which were synthesized on the basis of the pharmacophore of ROS-1 and evaluated for anti-proliferative activity. For this, the in silico receptor–ligand pharmacophore model of ROS-1, previously published by our own group, was utilized to screen out an in-house database of small molecule heterocycles. Docking analysis of the selected compounds was carried out within the active site of wild-type (WT) ROS-1 as well as Gly2032Arg mutant ROS-1 protein, which confirmed the retention of conserved interaction between selected molecules and hinge region amino acids Glu2027 and Met2029. Docking was followed by molecular dynamics simulations for the stability of the complexes and calculation of the MM-GBSA score for binding affinity. Finally, compounds were synthesized and the anti-proliferative potential of compounds was evaluated using the A549 cell line. Compounds 3a and 3b presented significant GI
50 values between 23.0 and 25.4 μM, among all the tested compounds. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
8. Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review.
- Author
-
Raju, Baddipadige, Choudhary, Shalki, Narendra, Gera, Verma, Himanshu, and Silakari, Om
- Subjects
DRUG resistance in cancer cells ,CANCER cells ,DRUG resistance ,ENZYMES ,ANTINEOPLASTIC agents - Abstract
Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these in-silico tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
9. Addressing selectivity issues of aldose reductase 2 inhibitors for the management of diabetic complications.
- Author
-
Kumar, Manoj, Choudhary, Shalki, Singh, Pankaj Kumar, and Silakari, Om
- Published
- 2020
- Full Text
- View/download PDF
10. Butterfly structure: a scaffold of therapeutic importance.
- Author
-
Choudhary, Shalki and Silakari, Om
- Published
- 2020
- Full Text
- View/download PDF
11. Decoding the signature of molecular mechanism involved in mutation associated resistance to 1, 3-benzothiazin-4-ones (Btzs) based DprE1 inhibitors using BTZ043 as a reference drug.
- Author
-
Verma, Himanshu, Choudhary, Shalki, Singh, Pankaj Kumar, Kashyap, Aanchal, and Silakari, Om
- Subjects
MUTANT proteins ,DRUG resistance ,BAND gaps ,CRYSTAL structure ,HOMOLOGY (Biology) - Abstract
Different resistant strains of M. tuberculosis (Mtb) highlight the urgent need of novel anti-tubercular drugs. In mycobacteria, decaprenyl-phosphoryl-β-D-ribose 2'-oxidase (DprE1) is an appealing enzyme to target as it is involved in the biosynthesis of cell wall component arabinogalactan.1, 3-benzothiazin-4-ones (BTZs) based drugs are promising irreversible inhibitors of DprE1. However, a single point mutation of Cys387Ser in DprE1 results in the development of resistance to these drugs. Herein, we made an effort to decode the molecular mechanism of Cys387Ser DprE1 mutation associated resistance in Mtb against BTZs using different in silico techniques. Since the 3D crystal structure of mutant Cys387Ser protein is not yet been solved, thus the homology model was also developed using 4P8N as a template protein with 99.8% homology with the target protein. The computational results suggested that the factors like HOMO–LUMO energy gap, Burgi-Dunitz angle and distance support the covalent inhibition of wild DprE1 by 1, 3-benzothiazin-4-ones class of drugs, using BTZ043 as a reference drug and the same factors support the cause of resistance in case of Cys387Ser mutation. On the basis of these results, it was concluded that BTZ043 can efficiently inhibit the wild type DprE1 than mutant DprE1. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
12. Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it.
- Author
-
Verma, Himanshu, Singh Bahia, Malkeet, Choudhary, Shalki, Kumar Singh, Pankaj, and Silakari, Om
- Subjects
PRODRUGS ,DRUG resistance in cancer cells ,CYTOCHROME P-450 CYP2D6 - Abstract
Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
13. Identification of 2‐benzoxazolinone derivatives as lead against molecular targets of diabetic complications.
- Author
-
Vyas, Bhawna, Choudhary, Shalki, Singh, Pankaj Kumar, Singh, Baldev, Bahadur, Renu, Malik, Ashok Kumar, and Silakari, Om
- Subjects
BENZOXAZOLINONE ,DIABETES complications ,ALDOSE reductase ,ADVANCED glycation end-products ,CHEMICAL synthesis - Abstract
Diabetic complications follow multiple pathophysiological pathways involving aldose reductase (ALR2)‐mediated polyol pathway, advanced glycation end products (AGEs) and reactive oxygen species formation. Literature suggests ALR2 inhibitors such as epalrestat to possess significant potential in retinopathy and neuropathy. Thus, in this study, multiple pathophysiology directed molecules targeting ALR2, AGEs and free radicals formation were designed using in silico techniques. Initially, database was screened via in silico tools to obtain hits with affinity for the catalytic domain of ALR2. Additional focus was laid on the presence of structural attributes responsible for AGE's inhibitory and anti‐oxidant potential. Out of obtained hits, 2‐benzoxazolinone scaffold was selected and ten derivatives were synthesized accordingly. Finally, the synthesized molecules were evaluated for their ALR2 and AGEs inhibitory activities along with free radical scavenging potency. Ten 2‐benzoxazolinone‐based derivatives were synthesized on the basis of in silico analysis and further evaluated in vitro for their aldose reductase (ALR2) inhibitory, advanced glycation end products (AGEs) inhibitory and free radical scavenging activities. Among all synthesized molecules, compound BV‐4 displayed best activity for all mentioned targets. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.