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Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity.
Interdiscip Sci. 2019 Jun; 11(2):191-205.IS

Abstract

Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q2) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Gupta N
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, Gujarat, India.
Vyas VK
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, Gujarat, India.
Patel BD
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, Gujarat, India.
Ghate M
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, Gujarat, India. ghate72@gmail.com.

MeSH

Anti-Bacterial AgentsCatalytic DomainDrug DesignEnzyme ActivatorsFlavinsHydrogen BondingHydrophobic and Hydrophilic InteractionsImidazolesMolecular Docking SimulationNitroreductasesQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28895050

Citation

Gupta, Nirzari, et al. "Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based On 3D QSAR, HQSAR, and Docking Study With in Silico Prediction of Activity and Toxicity." Interdisciplinary Sciences, Computational Life Sciences, vol. 11, no. 2, 2019, pp. 191-205.
Gupta N, Vyas VK, Patel BD, et al. Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity. Interdiscip Sci. 2019;11(2):191-205.
Gupta, N., Vyas, V. K., Patel, B. D., & Ghate, M. (2019). Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity. Interdisciplinary Sciences, Computational Life Sciences, 11(2), 191-205. https://doi.org/10.1007/s12539-017-0256-1
Gupta N, et al. Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based On 3D QSAR, HQSAR, and Docking Study With in Silico Prediction of Activity and Toxicity. Interdiscip Sci. 2019;11(2):191-205. PubMed PMID: 28895050.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity. AU - Gupta,Nirzari, AU - Vyas,Vivek K, AU - Patel,Bhumika D, AU - Ghate,Manjunath, Y1 - 2017/09/11/ PY - 2016/09/08/received PY - 2017/08/01/accepted PY - 2017/07/29/revised PY - 2017/9/13/pubmed PY - 2019/12/21/medline PY - 2017/9/13/entrez KW - 3D QSAR KW - Deazaflavin-dependent nitroreductase (Ddn) KW - Docking KW - HQSAR KW - In silico ADMET KW - Mycobacterium tuberculosis SP - 191 EP - 205 JF - Interdisciplinary sciences, computational life sciences JO - Interdiscip Sci VL - 11 IS - 2 N2 - Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q2) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis. SN - 1867-1462 UR - https://www.unboundmedicine.com/medline/citation/28895050/Design_of_2_Nitroimidazooxazine_Derivatives_as_Deazaflavin_Dependent_Nitroreductase__Ddn__Activators_as_Anti_Mycobacterial_Agents_Based_on_3D_QSAR_HQSAR_and_Docking_Study_with_In_Silico_Prediction_of_Activity_and_Toxicity_ DB - PRIME DP - Unbound Medicine ER -