Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
- Diallo, Bakary N, Swart, Tarryn, Hoppe, Heinrich C, Tastan Bishop, Özlem, Lobb, Kevin A
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021
- Authors: Diallo, Bakary N , Swart, Tarryn , Hoppe, Heinrich C , Tastan Bishop, Özlem , Lobb, Kevin A
- Date: 2021
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/177531 , vital:42830 , https://doi.org/10.1038/s41598-020-80722-2
- Description: Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings.
- Full Text:
- Date Issued: 2021
In silico study of Plasmodium 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB:
- Diallo, Bakary N, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- Full Text:
- Date Issued: 2019
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162687 , vital:40973 , https://doi.org/10.21955/aasopenres.1114960.1
- Description: In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools.
- Full Text:
- Date Issued: 2019
Novel potential antimalarials through drug repurposing and multitargeting: a Computational Approach
- Diallo, Bakary N, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
- Authors: Diallo, Bakary N , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162676 , vital:40972 , https://doi.org/10.21955/aasopenres.1114955.1
- Description: This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs.
- Full Text:
- Date Issued: 2019
SANCDB: an update on South African natural compounds and their readily available analogs
- Diallo, Bakary N, Glenister, Michael, Musyoka, Thommas M, Lobb, Kevin A, Taştan Bishop, Özlem
- Authors: Diallo, Bakary N , Glenister, Michael , Musyoka, Thommas M , Lobb, Kevin A , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451154 , vital:75023 , xlink:href="https://doi.org/10.1186/s13321-021-00514-2"
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
- Authors: Diallo, Bakary N , Glenister, Michael , Musyoka, Thommas M , Lobb, Kevin A , Taştan Bishop, Özlem
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451154 , vital:75023 , xlink:href="https://doi.org/10.1186/s13321-021-00514-2"
- Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
- Full Text:
- Date Issued: 2021
Oral Phytothymol ameliorates the stress induced IBS symptoms
- Subramaniyam, Selvaraj, Yang, Shuyou, Diallo, Bakary N, Fanshu, Xu, Lei, Luo, Li, Chong, Tastan Bishop, Özlem, Bhattacharyya, Sanjib
- Authors: Subramaniyam, Selvaraj , Yang, Shuyou , Diallo, Bakary N , Fanshu, Xu , Lei, Luo , Li, Chong , Tastan Bishop, Özlem , Bhattacharyya, Sanjib
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/426034 , vital:72308 , xlink:href="https://doi.org/10.1038/s41598-020-70420-4"
- Description: Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT3AR expression level while thymol treatment normalized the 5-HT3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT3AR. Our study suggest that thymol improves IBS symptoms through 5-HT3AR, could be useful for the treatment of IBS.
- Full Text:
- Date Issued: 2020
- Authors: Subramaniyam, Selvaraj , Yang, Shuyou , Diallo, Bakary N , Fanshu, Xu , Lei, Luo , Li, Chong , Tastan Bishop, Özlem , Bhattacharyya, Sanjib
- Date: 2020
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/426034 , vital:72308 , xlink:href="https://doi.org/10.1038/s41598-020-70420-4"
- Description: Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT3AR expression level while thymol treatment normalized the 5-HT3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT3AR. Our study suggest that thymol improves IBS symptoms through 5-HT3AR, could be useful for the treatment of IBS.
- Full Text:
- Date Issued: 2020
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