A New Synthetic Method for Tetraazatricyclic Derivatives and Evaluation of Their Biological Properties
- Odame, Felix, Betz, Richard, Hosten, Eric C, Krause, Jason, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D, Sayed, Yasien, Frost, P Carminita, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Betz, Richard , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, P Carminita , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123189 , vital:35413 , https://doi.org/10.1002/slct.201802930
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2018
- Authors: Odame, Felix , Betz, Richard , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, P Carminita , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123189 , vital:35413 , https://doi.org/10.1002/slct.201802930
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2018
Characterization and computational studies of a co-crystal of 2-aminobenzimidazole and 2-[(benzoylcarbamothioyl) amino] propanoic acid
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447030 , vital:74578 , xlink:href="https://doi.org/10.1134/S0022476618050268"
- Description: A novel co-crystal of 2-aminobenzimidazole and 2-[(benzoylcarbamothioyl)amino] propanoic acid is synthesized and characterized by spectroscopy, elemental analysis, GC-MS, and single crystal XRD. A computation of the structures involved in the formation of the co-crystal are carried out and their contribution to reactivity is explained.
- Full Text:
- Date Issued: 2018
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447030 , vital:74578 , xlink:href="https://doi.org/10.1134/S0022476618050268"
- Description: A novel co-crystal of 2-aminobenzimidazole and 2-[(benzoylcarbamothioyl)amino] propanoic acid is synthesized and characterized by spectroscopy, elemental analysis, GC-MS, and single crystal XRD. A computation of the structures involved in the formation of the co-crystal are carried out and their contribution to reactivity is explained.
- Full Text:
- Date Issued: 2018
Exploring molecular insights into the interaction mechanism of cholesterol derivatives with the Mce4A: A combined spectroscopic and molecular dynamic simulation studies
- Khan, Shagufta, Khan, Faez I, Khan, Parvez, Hasan, Gulam M, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Khan, Shagufta , Khan, Faez I , Khan, Parvez , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447041 , vital:74579 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.12.160"
- Description: Mammalian cell entry protein (Mce4A) is a member of MCE-family, and is being considered as a potential drug target of Mycobacterium tuberculosis infection because it is required for invasion and latent survival of pathogen by utilizing host's cholesterol. In the present study, we performed molecular docking followed by 100 ns MD simulation studies to understand the mechanism of interaction of Mce4A to the cholesterol derivatives and probucol. The selected ligands, cholesterol, 25-hydroxycholesterol, 5-cholesten-3β-ol-7-one and probucol bind to the predicted active site cavity of Mce4A, and complexes remain stable during entire simulation of 100 ns. In silico studies were further validated by fluorescence-binding studies to calculate actual binding affinity and number of binding site(s). The non-toxicity of all ligands was confirmed on human monocytic cell (THP1) by MTT assay. This work provides a deeper insight into the mechanism of interaction of Mce4A to cholesterol derivatives, which may be further exploited to design potential and specific inhibitors to ameliorate the Mycobacterium pathogenesis.
- Full Text:
- Date Issued: 2018
- Authors: Khan, Shagufta , Khan, Faez I , Khan, Parvez , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447041 , vital:74579 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.12.160"
- Description: Mammalian cell entry protein (Mce4A) is a member of MCE-family, and is being considered as a potential drug target of Mycobacterium tuberculosis infection because it is required for invasion and latent survival of pathogen by utilizing host's cholesterol. In the present study, we performed molecular docking followed by 100 ns MD simulation studies to understand the mechanism of interaction of Mce4A to the cholesterol derivatives and probucol. The selected ligands, cholesterol, 25-hydroxycholesterol, 5-cholesten-3β-ol-7-one and probucol bind to the predicted active site cavity of Mce4A, and complexes remain stable during entire simulation of 100 ns. In silico studies were further validated by fluorescence-binding studies to calculate actual binding affinity and number of binding site(s). The non-toxicity of all ligands was confirmed on human monocytic cell (THP1) by MTT assay. This work provides a deeper insight into the mechanism of interaction of Mce4A to cholesterol derivatives, which may be further exploited to design potential and specific inhibitors to ameliorate the Mycobacterium pathogenesis.
- Full Text:
- Date Issued: 2018
Investigation of molecular mechanism of recognition between citral and MARK4: A newer therapeutic approach to attenuate cancer cell progression
- Naz, Farha, Khan, Faez I, Mohammad, Taj, Khan, Parvez, Manzoor, Saaliqa, Hasan, Gulam M, Lobb, Kevin A, Luqman, Suaib, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Naz, Farha , Khan, Faez I , Mohammad, Taj , Khan, Parvez , Manzoor, Saaliqa , Hasan, Gulam M , Lobb, Kevin A , Luqman, Suaib , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447967 , vital:74687 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.10.143"
- Description: Microtubule affinity regulating kinase 4 (MARK4) is a member of AMP-activated protein kinase, found to be involved in apoptosis, inflammation and many other regulatory pathways. Since, its aberrant expression is directly associated with the cell cycle and thus cancer. Therefore, MARK4 is being considered as a potential drug target for cancer therapy. Here, we investigated the mechanism of inhibition of MARK4 activity by citral. Docking studies suggested that citral effectively binds to the active site cavity, and complex is stabilized by several interactions. We further performed molecular dynamics simulation of MARK4-citral complex under explicit water condition for 100 ns and observed that binding of citral to MARK4 was quite stable. Fluorescence binding studies suggested that citral strongly binds to MARK4 and thereby inhibits its enzyme activity which was measured by the kinase inhibition assay. We further performed MTT assay and observed that citral inhibits proliferation of breast cancer cell line MCF-7. This work provides a newer insight into the use of citral as novel cancer therapeutics through the MARK4 inhibition. Results may be employed to design novel therapeutic molecule using citral as a scaffold for MARK4 inhibition to fight related diseases.
- Full Text:
- Date Issued: 2018
- Authors: Naz, Farha , Khan, Faez I , Mohammad, Taj , Khan, Parvez , Manzoor, Saaliqa , Hasan, Gulam M , Lobb, Kevin A , Luqman, Suaib , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447967 , vital:74687 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.10.143"
- Description: Microtubule affinity regulating kinase 4 (MARK4) is a member of AMP-activated protein kinase, found to be involved in apoptosis, inflammation and many other regulatory pathways. Since, its aberrant expression is directly associated with the cell cycle and thus cancer. Therefore, MARK4 is being considered as a potential drug target for cancer therapy. Here, we investigated the mechanism of inhibition of MARK4 activity by citral. Docking studies suggested that citral effectively binds to the active site cavity, and complex is stabilized by several interactions. We further performed molecular dynamics simulation of MARK4-citral complex under explicit water condition for 100 ns and observed that binding of citral to MARK4 was quite stable. Fluorescence binding studies suggested that citral strongly binds to MARK4 and thereby inhibits its enzyme activity which was measured by the kinase inhibition assay. We further performed MTT assay and observed that citral inhibits proliferation of breast cancer cell line MCF-7. This work provides a newer insight into the use of citral as novel cancer therapeutics through the MARK4 inhibition. Results may be employed to design novel therapeutic molecule using citral as a scaffold for MARK4 inhibition to fight related diseases.
- Full Text:
- Date Issued: 2018
Iron (iii) porphyrin electrocatalyzed enantioselective carbon-chloride bond cleavage of hexachlorocyclohexanes (HCHs): combined experimental investigation and theoretical calculations
- Liang, Xu, Li, Minzhi, Mack, John, Lobb, Kevin A, Zhu, Weihua
- Authors: Liang, Xu , Li, Minzhi , Mack, John , Lobb, Kevin A , Zhu, Weihua
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447979 , vital:74688 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2018/dt/c8dt02510j"
- Description: Enantioselective electrocatalysis of α-, β-, γ- and δ-hexachlorocyclohexanes (HCHs) by tetrakis-pentafluorophenyl-Fe(III)porphyrin is described. The first example of the combined use of electrochemical measurements and theoretical calculations to determine the mechanism of the enantioselective C–Cl bond cleavage of the electrocatalysis is reported. The electrochemical measurements demonstrate that the reactivity of the HCHs follows the order γ-HCH > α-HCH > δ-HCH > β-HCH. Steric considerations and a molecular orbital theory approach can be used to rationalize the enantioselective nature of the catalysis based on the ease of approach of each Cl atom to the central Fe(I) ion and a consideration of the nodes on the C–Cl bonds that weaken these bonds in a manner that results in bond cleavage and the formation of an Fe–Cl bond.
- Full Text:
- Date Issued: 2018
- Authors: Liang, Xu , Li, Minzhi , Mack, John , Lobb, Kevin A , Zhu, Weihua
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447979 , vital:74688 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2018/dt/c8dt02510j"
- Description: Enantioselective electrocatalysis of α-, β-, γ- and δ-hexachlorocyclohexanes (HCHs) by tetrakis-pentafluorophenyl-Fe(III)porphyrin is described. The first example of the combined use of electrochemical measurements and theoretical calculations to determine the mechanism of the enantioselective C–Cl bond cleavage of the electrocatalysis is reported. The electrochemical measurements demonstrate that the reactivity of the HCHs follows the order γ-HCH > α-HCH > δ-HCH > β-HCH. Steric considerations and a molecular orbital theory approach can be used to rationalize the enantioselective nature of the catalysis based on the ease of approach of each Cl atom to the central Fe(I) ion and a consideration of the nodes on the C–Cl bonds that weaken these bonds in a manner that results in bond cleavage and the formation of an Fe–Cl bond.
- Full Text:
- Date Issued: 2018
Mechanistic insights into the urea-induced denaturation of kinase domain of human integrin linked kinase
- Syed, Sunayana B, Khan, Faez I, Khan, Sabab H, Srivastava, Saurabha, Hasan, Gulam M, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Syed, Sunayana B , Khan, Faez I , Khan, Sabab H , Srivastava, Saurabha , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448013 , vital:74691 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.12.164"
- Description: Integrin-linked kinase (ILK), a ubiquitously expressed intracellular Ser/Thr protein kinase, plays a major role in the oncogenesis and tumour progression. The conformational stability and unfolding of kinase domain of ILK (ILK193–446) was examined in the presence of increasing concentrations of urea. The stability parameters of the urea-induced denaturation were measured by monitoring changes in [θ]222 (mean residue ellipticity at 222 nm), difference absorption coefficient at 292 nm (Δε292) and intrinsic fluorescence emission intensity at pH 7.5 and 25 ± 0.1 °C. The urea-induced denaturation was found to be reversible. The protein unfolding transition occurred in the urea concentration range 3.0–7.0 M. A coincidence of normalized denaturation curves of optical properties ([θ]222, Δε292 and λmax, the wavelength of maximum emission intensity) suggested that ureainduced denaturation of kinase domain of ILK is a two-state process. We further performed molecular dynamics simulation for 100 ns to see the effect of urea on structural stability of kinase domain of ILK at atomic level. Structural changes with increasing concentrations of urea were analysed, and we observed a significant increase in the root mean square deviation, root mean square fluctuations, solvent accessible surface area and radius of gyration. A correlation was observed between in vitro and in silico studies.
- Full Text:
- Date Issued: 2018
- Authors: Syed, Sunayana B , Khan, Faez I , Khan, Sabab H , Srivastava, Saurabha , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448013 , vital:74691 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2017.12.164"
- Description: Integrin-linked kinase (ILK), a ubiquitously expressed intracellular Ser/Thr protein kinase, plays a major role in the oncogenesis and tumour progression. The conformational stability and unfolding of kinase domain of ILK (ILK193–446) was examined in the presence of increasing concentrations of urea. The stability parameters of the urea-induced denaturation were measured by monitoring changes in [θ]222 (mean residue ellipticity at 222 nm), difference absorption coefficient at 292 nm (Δε292) and intrinsic fluorescence emission intensity at pH 7.5 and 25 ± 0.1 °C. The urea-induced denaturation was found to be reversible. The protein unfolding transition occurred in the urea concentration range 3.0–7.0 M. A coincidence of normalized denaturation curves of optical properties ([θ]222, Δε292 and λmax, the wavelength of maximum emission intensity) suggested that ureainduced denaturation of kinase domain of ILK is a two-state process. We further performed molecular dynamics simulation for 100 ns to see the effect of urea on structural stability of kinase domain of ILK at atomic level. Structural changes with increasing concentrations of urea were analysed, and we observed a significant increase in the root mean square deviation, root mean square fluctuations, solvent accessible surface area and radius of gyration. A correlation was observed between in vitro and in silico studies.
- Full Text:
- Date Issued: 2018
Seed extract of Psoralea corylifolia and its constituent bakuchiol impairs AHL-based quorum sensing and biofilm formation in food-and human-related pathogens
- Husain, Fohad M, Ahmad, Iqbal, Khan, Faez I, Al-Shabib, Nasser A, Baig, Mohammad H, Hussain, Afzal, Rehman, Md T, Alajmi, Mohamed F, Lobb, Kevin A
- Authors: Husain, Fohad M , Ahmad, Iqbal , Khan, Faez I , Al-Shabib, Nasser A , Baig, Mohammad H , Hussain, Afzal , Rehman, Md T , Alajmi, Mohamed F , Lobb, Kevin A
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447182 , vital:74590 , xlink:href="https://doi.org/10.3389/fcimb.2018.00351"
- Description: The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti-QS property in the Chromobacterium violaceum 12472 strain.
- Full Text:
- Date Issued: 2018
- Authors: Husain, Fohad M , Ahmad, Iqbal , Khan, Faez I , Al-Shabib, Nasser A , Baig, Mohammad H , Hussain, Afzal , Rehman, Md T , Alajmi, Mohamed F , Lobb, Kevin A
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447182 , vital:74590 , xlink:href="https://doi.org/10.3389/fcimb.2018.00351"
- Description: The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti-QS property in the Chromobacterium violaceum 12472 strain.
- Full Text:
- Date Issued: 2018
Synthesis, characterization and DPPH scavenging activity of some benzimidazole derivatives
- Odame, Felix, Krause, Jason, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R, Frost, Carminita L
- Authors: Odame, Felix , Krause, Jason , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R , Frost, Carminita L
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447209 , vital:74592 , xlink:href="https://dx.doi.org/10.4314/bcse.v32i2.8 "
- Description: A base-catalyzed conversion of aldehydes to benzimidazoles has been achieved. The compounds have been characterized by IR, NMR, micoranalysis, and GC-MS. The reaction for the formation of benzimidazoles has been monitored with 1 H NMR and IR. The crystal structures of two derivatives, 2-(2- chlorophenyl)-1H-benzimidazole and 2-(1H-benzimidazol-2-yl)-4-nitrophenol, are presented. A study of the DPPH scavenging activity of these compounds showed that 2-(1H-benzimidazol-2-yl)phenol (2), 2-p-tolyl-1Hbenzimidazole (3) and 2-(4-methoxyphenyl)-1H-benzimidazole (7) gave IC50 values 1974, 773 and 800 µM.
- Full Text:
- Date Issued: 2018
- Authors: Odame, Felix , Krause, Jason , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R , Frost, Carminita L
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447209 , vital:74592 , xlink:href="https://dx.doi.org/10.4314/bcse.v32i2.8 "
- Description: A base-catalyzed conversion of aldehydes to benzimidazoles has been achieved. The compounds have been characterized by IR, NMR, micoranalysis, and GC-MS. The reaction for the formation of benzimidazoles has been monitored with 1 H NMR and IR. The crystal structures of two derivatives, 2-(2- chlorophenyl)-1H-benzimidazole and 2-(1H-benzimidazol-2-yl)-4-nitrophenol, are presented. A study of the DPPH scavenging activity of these compounds showed that 2-(1H-benzimidazol-2-yl)phenol (2), 2-p-tolyl-1Hbenzimidazole (3) and 2-(4-methoxyphenyl)-1H-benzimidazole (7) gave IC50 values 1974, 773 and 800 µM.
- Full Text:
- Date Issued: 2018
The determination of CHARMM force field parameters for the Mg2+ containing HIV-1 integrase:
- Musyoka, Thommas M, Tastan Bishop, Özlem, Lobb, Kevin A, Moses, Vuyani
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
Unravelling the unfolding mechanism of human integrin linked kinase by GdmCl-induced denaturation
- Syed, Sunayana B, Khan, Faez I, Khan, Sabab H, Srivastava, Saurabha, Hasan, Gulam M, Lobb, Kevin A, Islam, Asimul, Hassan, M Imtaiyaz, Ahmad, Faizan
- Authors: Syed, Sunayana B , Khan, Faez I , Khan, Sabab H , Srivastava, Saurabha , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Hassan, M Imtaiyaz , Ahmad, Faizan
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447220 , vital:74593 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2018.06.025"
- Description: Integrin-linked kinase (ILK) is a ubiquitously expressed Ser/Thr kinase which plays significant role in the cell-matrix interactions and growth factor signalling. In this study, guanidinium chloride (GdmCl)-induced unfolding of kinase domain of ILK (ILK193–446) was carried out at pH 7.5 and 25 °C. Eventually, denaturation curves of mean residue ellipticity at 222 nm ([θ]222) and fluorescence emission spectrum were analysed to estimate stability parameters. The optical properties maximum emission (λmax) and difference absorption coefficient at 292 nm (Δε292) were analysed. The denaturation curve was measured only in the GdmCl molar concentration ranging 3.0–4.2 M because protein was aggregating below 3.0 M of GdmCl concentrations. The denaturation process of ILK193–446 was found as reversible at [GdmCl] ≥ 3.0 M. Moreover, a coincidence of normalized denaturation curves of optical properties ([θ]222, Δε292 and λmax) suggesting that GdmCl-induced denaturation of ILK193–446 is a two-state process. In addition, 100 ns molecular dynamics simulations were performed to see the effects of GdmCl on the structure and stability of ILK193–446. Both the spectroscopic and molecular dynamics ap proaches provided clear insights into the stability and conformational properties of ILK.
- Full Text:
- Date Issued: 2018
- Authors: Syed, Sunayana B , Khan, Faez I , Khan, Sabab H , Srivastava, Saurabha , Hasan, Gulam M , Lobb, Kevin A , Islam, Asimul , Hassan, M Imtaiyaz , Ahmad, Faizan
- Date: 2018
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447220 , vital:74593 , xlink:href="https://doi.org/10.1016/j.ijbiomac.2018.06.025"
- Description: Integrin-linked kinase (ILK) is a ubiquitously expressed Ser/Thr kinase which plays significant role in the cell-matrix interactions and growth factor signalling. In this study, guanidinium chloride (GdmCl)-induced unfolding of kinase domain of ILK (ILK193–446) was carried out at pH 7.5 and 25 °C. Eventually, denaturation curves of mean residue ellipticity at 222 nm ([θ]222) and fluorescence emission spectrum were analysed to estimate stability parameters. The optical properties maximum emission (λmax) and difference absorption coefficient at 292 nm (Δε292) were analysed. The denaturation curve was measured only in the GdmCl molar concentration ranging 3.0–4.2 M because protein was aggregating below 3.0 M of GdmCl concentrations. The denaturation process of ILK193–446 was found as reversible at [GdmCl] ≥ 3.0 M. Moreover, a coincidence of normalized denaturation curves of optical properties ([θ]222, Δε292 and λmax) suggesting that GdmCl-induced denaturation of ILK193–446 is a two-state process. In addition, 100 ns molecular dynamics simulations were performed to see the effects of GdmCl on the structure and stability of ILK193–446. Both the spectroscopic and molecular dynamics ap proaches provided clear insights into the stability and conformational properties of ILK.
- Full Text:
- Date Issued: 2018
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