Applications of Computers in Pharmaceutical Product Formulation

Deb, Pran Kishore; Al-Attraqchi, Omar; Al-Qattan, Mohammed Nooraldeen; Mailavaram, Raghu Prasad; Tekade, Rakesh K.

doi:10.1016/b978-0-12-814421-3.00019-1

Cited by 17 publications

(7 citation statements)

References 103 publications

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“…The best computational method that can simulate the ligand binding to a target while accounting for full target and ligand flexibility and explicit solvent effect is MD simulations 93–95 . Therefore, MD was utilised to study the binding stability and interactions of a virtual complex of Pks13-TE and compound 3a .…”

Section: Resultsmentioning

confidence: 99%

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Deb

Al-Shar’i

Venugopala

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives ( 3a–3i ) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively. To understand the mechanism of action of these compounds ( 3a–3i ) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a , promising leads worthy of further optimisation.

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Section: Resultsmentioning

confidence: 99%

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Deb

Al-Shar’i

Venugopala

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The promising activities of the designed compounds are very encouraging to undertake prospective optimisation cycles. However, it is highly recommended to optimise the ADMET properties for a lead compound early in the development stage to reduce later problems due to unfavourable ADMET characteristics 53 , 54 . Based on the in silico calculated ADME and toxicity parameters ( Table 3 ), all the compounds are showing acceptable ADMET profile which makes them worthy of further optimisation towards achieving the desired drug-like properties.…”

Section: Resultsmentioning

confidence: 99%

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

Venugopala

Chandrashekharappa

Deb

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 mg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC ¼ 16-64 mg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

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“…Molecular docking studies are considered an invaluable in silico approach to correlate the in vitro structure-activity relationship (SAR) of chemical compounds [63]. To gain insight into the inhibitory activity of indolizines (5a-e), we investigated their key interactions with the COX-2 receptor through a computational approach.…”

Section: Computational Studiesmentioning

confidence: 99%

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives

et al. 2021

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The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

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Applications of Computers in Pharmaceutical Product Formulation

Cited by 17 publications

References 103 publications

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives

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