DFT Based QSAR/QSPR Models in the Development of Novel Anti-tuberculosis Drugs Targeting Mycobacterium tuberculosis

Rajkhowa, Sanchaita; Deka, Ramesh Chandra

doi:10.2174/1381612819666131118165824

Cited by 15 publications

(8 citation statements)

References 91 publications

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“…Antibiotic limitations are functions of physico-chemical properties that can be dialed-in by medicinal chemistry, to some extent [ 45 ]. For example, QSAR-based design has made significant strides toward rational design of INH derivatives [ 46 , 47 ], but is almost exclusively focused on lowering MIC [ 46 – 48 ]. A systematic evaluation of the penetration of new drug candidates to the site of action most relevant for their sterilizing activity will undoubtedly help shorten TB treatment and minimize the number of agents required to achieve a sterile cure [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

et al. 2015

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BackgroundImprovement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes.ResultsWe pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment.ConclusionsOur systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0221-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

et al. 2015

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“…DFT analysis is crucial for determining functions like electron affinities, ionization potentials, orbital energies and molecular structures [30] . To define the reactivity of a chemical species, HOMO‐LUMO frontier orbitals are very important.…”

Section: Resultsmentioning

confidence: 99%

“…DFT analysis is crucial for determining functions like electron affinities, ionization potentials, orbital energies and molecular structures. [30] To define the reactivity of a chemical species, HOMO-LUMO frontier orbitals are very important. A molecule with a higher value of E HOMO gives electrons to molecules with low energy and vacant molecular orbital.…”

Section: Dft Analysismentioning

confidence: 99%

Elucidating the Interaction and Stability of Withanone and Withaferin‐A with Human Serum Albumin, Lysozyme and Hemoglobin Using Computational Biophysical Modeling

2022

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Withania somnifera consists of various bioactive compounds, of which withanone (WT−N) and withaferin‐A (WT−A) are known to have many therapeutic properties. To understand drug metabolism and transportation methods, binding of endogenous and exogenous ingredients with transport proteins is of utmost importance. Therefore, to perceive the molecular recognition mechanism of WT−N and WT−A, the association of human serum albumin, human hemoglobin and human lysozyme with WT−N and WT−A were examined, using various in silico techniques. For our study, we have employed both quantum mechanics and molecular mechanics approaches. Resultantly, drug‐like properties and reactivity were calculated with WT−N and WT−A being the most reactive among all the withanolides. The protein HSA in presence of WT−N showed more stability than that of WT−A. However, HL and Hb showed better stability with WT−A as compared to WT−N. Several non‐covalent interactions contributed the utmost part in the binding of WT−N and WT−A with the proteins. The MD simulation studies also showed evidence in the conformational changes and other dynamical properties of the three proteins with both the ligands. Finally, MM‐PBSA results confirmed the free binding energy of the complexes. Our study has provided a substantial recognition of bioactive molecules WT−N and WT−A binding with the carrier proteins, which can significantly affect the pharmacokinetics of these molecules.

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“…Lipophilicity has been the physicochemical parameter continually attracting prime interest in QSAR and SAR studies as a predominant descriptor of pharmacodynamic, pharmacokinetic and toxic aspects of the antimycobacterial drugs [ 33 , 34 , 35 , 36 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

et al. 2017

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Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a–h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a–h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a–h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a–h were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 μM indicated. The structure–antimycobacterial activity relationships of the analyzed 8a–h series are also discussed.

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DFT Based QSAR/QSPR Models in the Development of Novel Anti-tuberculosis Drugs Targeting Mycobacterium tuberculosis

Cited by 15 publications

References 91 publications

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Elucidating the Interaction and Stability of Withanone and Withaferin‐A with Human Serum Albumin, Lysozyme and Hemoglobin Using Computational Biophysical Modeling

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

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