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Article ; Online: Hybrid 2D/3D-quantitative structure-activity relationship and modeling studies perspectives of pepstatin A analogs as cathepsin D inhibitors.

Arodola, Olayide A / Soliman, Mahmoud Es

Future medicinal chemistry

2018 Volume 10, Issue 1, Page(s) 5–26

Abstract: Aim: Cathepsin D, one of the attractive targets in the treatment of breast cancer, has been implicated in HIV neuropathogenesis with potential proteolytic effects on chemokines. Methodology/result: Diverse modeling tools were used to reveal the key ... ...

Abstract	Aim: Cathepsin D, one of the attractive targets in the treatment of breast cancer, has been implicated in HIV neuropathogenesis with potential proteolytic effects on chemokines. Methodology/result: Diverse modeling tools were used to reveal the key structural features affecting the inhibitory activities of 78 pepstatin A analogs. Analyses were performed to investigate the stability, rationality and fluctuation of the analogs. Results showed a clear correlation between the experimental and predicted activities of the analogs as well as the variation in their activities relative to structural modifications. Conclusion: The insight gained from this study offers theoretical references for understanding the mechanism of action of cathepsin D and will aid in the design of more potent and clinically-relevant drugs. Graphical abstract [Formula: see text].
MeSH term(s)	Cathepsin D/antagonists & inhibitors ; Cathepsin D/metabolism ; Dose-Response Relationship, Drug ; Humans ; Models, Molecular ; Molecular Structure ; Pepstatins/chemical synthesis ; Pepstatins/chemistry ; Pepstatins/pharmacology ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Quantitative Structure-Activity Relationship ; Structure-Activity Relationship
Chemical Substances	Pepstatins ; Protease Inhibitors ; CTSD protein, human (EC 3.4.23.5) ; Cathepsin D (EC 3.4.23.5) ; pepstatin (V6Y2T27Q1U)
Language	English
Publishing date	2018
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2017-0077
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Quantum mechanics implementation in drug-design workflows: does it really help?

Arodola, Olayide A / Soliman, Mahmoud Es

Drug design, development and therapy

2017 Volume 11, Page(s) 2551–2564

Abstract: The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the ... ...

Abstract	The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry. However, the complexity of many protein-ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. The usefulness of quantum mechanics (QM) in drug-protein interaction cannot be overemphasized; however, this approach has little significance in some empirical methods. In this review, we discuss recent developments in, and application of, QM to medically relevant biomolecules. We critically discuss the different types of QM-based methods and their proposed application to incorporating them into drug-design and -discovery workflows while trying to answer a critical question: are QM-based methods of real help in drug-design and -discovery research and industry?
MeSH term(s)	Drug Design ; Drug Discovery/methods ; Drug Industry/methods ; Humans ; Ligands ; Molecular Dynamics Simulation ; Proteins/metabolism ; Quantum Theory ; Workflow
Chemical Substances	Ligands ; Proteins
Language	English
Publishing date	2017-08-31
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S126344
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An in-silico layer-by-layer adsorption study of the interaction between Rebaudioside A and the T1R2 human sweet taste receptor: modelling and biosensing perspectives.

Arodola, Olayide A / Kanchi, Suvardhan / Hloma, Phathisanani / Bisetty, Krishna / Asiri, Abdullah M / Inamuddin

Scientific reports

2020 Volume 10, Issue 1, Page(s) 18391

Abstract: The human sweet taste receptor (T1R2) monomer-a member of the G-protein coupled receptor family that detects a wide variety of chemically and structurally diverse sweet tasting molecules, is known to pose a significant threat to human health. Protein ... ...

Abstract	The human sweet taste receptor (T1R2) monomer-a member of the G-protein coupled receptor family that detects a wide variety of chemically and structurally diverse sweet tasting molecules, is known to pose a significant threat to human health. Protein that lack crystal structure is a challenge in structure-based protein design. This study focused on the interaction of the T1R2 monomer with rebaudioside A (Reb-A), a steviol glycoside with potential use as a natural sweetener using in-silico and biosensing methods. Herein, homology modelling, docking studies, and molecular dynamics simulations were applied to elucidate the interaction between Reb-A and the T1R2 monomer. In addition, the electrochemical sensing of the immobilised T1R2-Reb-A complex with zinc oxide nanoparticles (ZnONPs) and graphene oxide (GO) were assessed by testing the performance of multiwalled carbon nanotube (MWCNT) as an adsorbent experimentally. Results indicate a strong interaction between Reb-A and the T1R2 receptor, revealing the stabilizing interaction of the amino acids with the Reb-A by hydrogen bonds with the hydroxyl groups of the glucose moieties, along with a significant amount of hydrophobic interactions. Moreover, the presence of the MWCNT as an anchor confirms the adsorption strength of the T1R2-Reb-A complex onto the GO nanocomposite and supported with electrochemical measurements. Overall, this study could serve as a cornerstone in the development of electrochemical immunosensor for the detection of Reb-A, with applications in the food industry.
MeSH term(s)	Adsorption ; Biosensing Techniques ; Computer Simulation ; Diterpenes, Kaurane/chemistry ; Humans ; Models, Chemical ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; Receptors, G-Protein-Coupled/chemistry ; Sweetening Agents/chemistry ; Taste Buds/chemistry
Chemical Substances	Diterpenes, Kaurane ; Receptors, G-Protein-Coupled ; Sweetening Agents ; rebaudioside A (B3FUD0528F)
Language	English
Publishing date	2020-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-75123-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An in-silico layer-by-layer adsorption study of the interaction between Rebaudioside A and the T1R2 human sweet taste receptor

Olayide A. Arodola / Suvardhan Kanchi / Phathisanani Hloma / Krishna Bisetty / Abdullah M. Asiri / Inamuddin

Scientific Reports, Vol 10, Iss 1, Pp 1-

modelling and biosensing perspectives

2020 Volume 18

Abstract: Abstract The human sweet taste receptor (T1R2) monomer—a member of the G-protein coupled receptor family that detects a wide variety of chemically and structurally diverse sweet tasting molecules, is known to pose a significant threat to human health. ... ...

Abstract	Abstract The human sweet taste receptor (T1R2) monomer—a member of the G-protein coupled receptor family that detects a wide variety of chemically and structurally diverse sweet tasting molecules, is known to pose a significant threat to human health. Protein that lack crystal structure is a challenge in structure-based protein design. This study focused on the interaction of the T1R2 monomer with rebaudioside A (Reb-A), a steviol glycoside with potential use as a natural sweetener using in-silico and biosensing methods. Herein, homology modelling, docking studies, and molecular dynamics simulations were applied to elucidate the interaction between Reb-A and the T1R2 monomer. In addition, the electrochemical sensing of the immobilised T1R2-Reb-A complex with zinc oxide nanoparticles (ZnONPs) and graphene oxide (GO) were assessed by testing the performance of multiwalled carbon nanotube (MWCNT) as an adsorbent experimentally. Results indicate a strong interaction between Reb-A and the T1R2 receptor, revealing the stabilizing interaction of the amino acids with the Reb-A by hydrogen bonds with the hydroxyl groups of the glucose moieties, along with a significant amount of hydrophobic interactions. Moreover, the presence of the MWCNT as an anchor confirms the adsorption strength of the T1R2-Reb-A complex onto the GO nanocomposite and supported with electrochemical measurements. Overall, this study could serve as a cornerstone in the development of electrochemical immunosensor for the detection of Reb-A, with applications in the food industry.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular Dynamics Simulations of Ligand-Induced Flap Conformational Changes in Cathepsin-D-A Comparative Study.

Arodola, Olayide A / Soliman, Mahmoud E S

Journal of cellular biochemistry

2016 Volume 117, Issue 11, Page(s) 2643–2657

Abstract: The flap region in aspartic proteases is a unique structural feature to this class of enzymes, and found to have a profound impact on protein overall structure, function, and dynamics. Understanding the structure and dynamic behavior of the flap regions ... ...

Abstract	The flap region in aspartic proteases is a unique structural feature to this class of enzymes, and found to have a profound impact on protein overall structure, function, and dynamics. Understanding the structure and dynamic behavior of the flap regions is crucial in the design of selective inhibitors against aspartic proteases. Cathepsin-D, an aspartic protease enzyme, has been implicated in a long list of degenerative diseases as well as breast cancer progression. Presented herein, for the first time, is a comprehensive description of the conformational flap dynamics of cathepsin-D using a comparative 50 ns "multiple" molecular dynamics simulations. Diverse collective metrics were proposed to accurately define flap dynamics. These are distance d1 between the flap tips residues (Gly79 and Met301); dihedral angle ϕ; in addition to TriCα angles Gly79-Asp33-Asp223, θ1 , and Gly79-Asp223-Met301, θ2 . The maximum distance attained throughout the simulation was 17.42 and 11.47 Å for apo and bound cathepsin-D, respectively, while the minimum distance observed was 8.75 and 6.32 Å for apo and bound cathepsin-D, respectively. The movement of the flap as well as the twist of the active pocket can properly be explained by measuring the angle, θ1 , between Gly79-Asp33-Met301 and correlating it with the distance Cα of the flap tip residues. The asymmetrical opening of the binding cavity was best described by the large shift of -6.26° to +20.94° in the dihedral angle, ϕ, corresponding to the full opening of the flap at a range of 31-33 ns. A wide-range of post-dynamic analyses was also applied in this report to supplement our findings. We believe that this report would augment current efforts in designing potent structure-based inhibitors against cathepsin-D in the treatment of breast cancer and other degenerative diseases. J. Cell. Biochem. 117: 2643-2657, 2016. © 2016 Wiley Periodicals, Inc.
MeSH term(s)	Binding Sites ; Catalytic Domain ; Cathepsin D/chemistry ; Crystallography, X-Ray ; Humans ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Protein Conformation
Chemical Substances	Ligands ; Cathepsin D (EC 3.4.23.5)
Language	English
Publishing date	2016-11
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.25564
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses.

Arodola, Olayide A / Soliman, Mahmoud E S

Drug design, development and therapy

2015 Volume 9, Page(s) 6055–6065

Abstract: Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized ...

Abstract	Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, "loop docking" - an enhanced in-house developed molecular docking approach - followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG =-9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =-9.0, -8.6, and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Binding Sites ; Drug Design ; Drug Repositioning ; HIV Protease/chemistry ; HIV Protease/metabolism ; HIV Protease Inhibitors/chemistry ; HIV Protease Inhibitors/metabolism ; HIV Protease Inhibitors/pharmacology ; HIV-1/drug effects ; HIV-1/enzymology ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/chemistry ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Nelfinavir/chemistry ; Nelfinavir/metabolism ; Nelfinavir/pharmacology ; Protein Binding ; Protein Conformation ; Reproducibility of Results ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; HIV Protease Inhibitors ; HSP90 Heat-Shock Proteins ; HIV Protease (EC 3.4.23.-) ; p16 protease, Human immunodeficiency virus 1 (EC 3.4.23.-) ; Nelfinavir (HO3OGH5D7I)
Language	English
Publishing date	2015
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S87653
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses

Arodola OA / Soliman MES

Drug Design, Development and Therapy, Vol 2015, Iss default, Pp 6055-

2015 Volume 6065

Abstract: Olayide A Arodola, Mahmoud ES SolimanMolecular Modelling and Drug Design Lab, School of Health ...

Abstract	Olayide A Arodola, Mahmoud ES SolimanMolecular Modelling and Drug Design Lab, School of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban, South AfricaAbstract: Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, “loop docking” – an enhanced in-house developed molecular docking approach – followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG=−9.2kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1µM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG=−9.0, −8.6, and −8.5kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer.Keywords: binding free energy, loop docking, molecular dynamics, HIV-1 protease inhibitors, anticancer
Keywords	Medicine ; R ; Medicine (General) ; R5-920 ; Therapeutics. Pharmacology ; RM1-950
Subject code	540
Publishing date	2015-11-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hybrid 2D/3D-quantitative structure-activity relationship and modeling studies perspectives of pepstatin A analogs as cathepsin D inhibitors.

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Article ; Online: Quantum mechanics implementation in drug-design workflows: does it really help?

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Article ; Online: An in-silico layer-by-layer adsorption study of the interaction between Rebaudioside A and the T1R2 human sweet taste receptor: modelling and biosensing perspectives.

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Article ; Online: An in-silico layer-by-layer adsorption study of the interaction between Rebaudioside A and the T1R2 human sweet taste receptor

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Article ; Online: Molecular Dynamics Simulations of Ligand-Induced Flap Conformational Changes in Cathepsin-D-A Comparative Study.

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Article ; Online: Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses.

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Article ; Online: Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses

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