High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV
- Beg, Anam, Khan, Faez I, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Beg, Anam , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/${Handle} , vital:74587 , xlink:href="https://doi.org/10.1080/07391102.2018.1479310"
- Description: Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (−11.6 to −10.0 kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.
- Full Text:
- Date Issued: 2019
- Authors: Beg, Anam , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/${Handle} , vital:74587 , xlink:href="https://doi.org/10.1080/07391102.2018.1479310"
- Description: Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here, we have employed the knowledge of three-dimensional structure of CAMKIV to identify new inhibitors for possible therapeutic intervention. We have employed virtual high throughput screening of 12,500 natural compounds of Zinc database to screen the best possible inhibitors of CAMKIV. Subsequently, 40 compounds which showed significant docking scores (−11.6 to −10.0 kcal/mol) were selected and further filtered through Lipinski rule and drug likeness parameter to get best inhibitors of CAMKIV. Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions. Four compounds, ZINC02098378, ZINC12866674, ZINC04293413, and ZINC13403020, showing excellent binding affinity and drug likeness were subjected to molecular dynamics simulation to evaluate their mechanism of interaction and stability of protein-ligand complex. Our observations clearly suggesting that these selected ligands may be further employed for therapeutic intervention to address CAMKIV associated diseases.
- Full Text:
- Date Issued: 2019
Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4)
- Mohammad, Taj, Khan, Faez I, Lobb, Kevin A, Islam, Asimul, Ahmad, Faizan, Hassan, M Imtaiyaz
- Authors: Mohammad, Taj , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447159 , vital:74588 , xlink:href="https://doi.org/10.1080/07391102.2018.1468282"
- Description: Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.
- Full Text:
- Date Issued: 2019
- Authors: Mohammad, Taj , Khan, Faez I , Lobb, Kevin A , Islam, Asimul , Ahmad, Faizan , Hassan, M Imtaiyaz
- Date: 2019
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447159 , vital:74588 , xlink:href="https://doi.org/10.1080/07391102.2018.1468282"
- Description: Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.
- Full Text:
- Date Issued: 2019
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
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
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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