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Article ; Online: Exploring the composition of protein-ligand binding sites for cancerous inhibitor of PP2A (CIP2A) by inhibitor guided binding analysis: paving a new way for the Discovery of drug candidates against triple negative breast cancer (TNBC).

Ibitoye, Oluwayimika / Ibrahim, Mahmoud A A / Soliman, Mahmoud E S

Journal of receptor and signal transduction research

2024 Volume 43, Issue 6, Page(s) 133–143

Abstract: Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach ... ...

Abstract	Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis
MeSH term(s)	Female ; Humans ; Lapatinib/therapeutic use ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Ligands ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/metabolism ; Transcription Factors ; Binding Sites ; Carcinogenesis ; Cell Line, Tumor
Chemical Substances	Lapatinib (0VUA21238F) ; Ligands ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Transcription Factors
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1230969-2
ISSN	1532-4281 ; 1079-9893
ISSN (online)	1532-4281
ISSN	1079-9893
DOI	10.1080/10799893.2023.2298903
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Article ; Online: Unravelling the Structural Mechanism of Action of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione in Dual-Targeting Tankyrase 1 and 2: A Novel Avenue in Cancer Therapy.

Peters, Xylia Q / Agoni, Clement / Soliman, Mahmoud E S

Cell biochemistry and biophysics

2022 Volume 80, Issue 3, Page(s) 505–518

Abstract: Tankyrase (TNKS) belonging to the poly(ADPribose) polymerase family, are known for their multi-functioning capabilities, and play an essential role in the Wnt β-catenin pathway and various other cellular processes. Although showing inhibitory potential ... ...

Abstract	Tankyrase (TNKS) belonging to the poly(ADPribose) polymerase family, are known for their multi-functioning capabilities, and play an essential role in the Wnt β-catenin pathway and various other cellular processes. Although showing inhibitory potential at a nanomolar level, the structural dual-inhibitory mechanism of the novel TNKS inhibitor, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, remains unexplored. By employing advanced molecular modeling, this study provides these insights. Results of sequence alignments of binding site residues identified conserved residues; GLY1185 and ILE1224 in TNKS-1 and PHE1035 and PRO1034 in TNKS-2 as crucial mediators of the dual binding mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Estimation of the binding free energy of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione showed estimated total energy of -43.88 kcal/mol and -30.79 kcal/mol towards TNKS-1 and 2, respectively, indicating favorable analogous dual binding as previously reported. Assessment of the conformational dynamics of TNKS-1 and 2 upon the binding of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione revealed similar structural changes characterized by increased flexibility and solvent assessible surface area of the residues inferring an analogous structural binding mechanism. Insights from this study show that peculiar, conserved residues are the driving force behind the dual inhibitory mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and could aid in the design of novel dual inhibitors of TNKS-1 and 2 with improved therapeutic properties.
MeSH term(s)	Humans ; Hydantoins ; Imidazolidines ; Neoplasms ; Tankyrases/chemistry ; Tankyrases/metabolism ; Wnt Signaling Pathway
Chemical Substances	Hydantoins ; Imidazolidines ; TNKS2 protein, human (EC 2.4.2.30) ; Tankyrases (EC 2.4.2.30) ; TNKS protein, human (EC 2.4.4.30)
Language	English
Publishing date	2022-05-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1357904-6
ISSN	1559-0283 ; 1085-9195
ISSN (online)	1559-0283
ISSN	1085-9195
DOI	10.1007/s12013-022-01076-2
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Zs.A 1498: Show issues

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Article ; Online: Multi-catalytic Sites Inhibition of Bcl2 Induces Expanding of Hydrophobic Groove: A New Avenue Towards Waldenström Macroglobulinemia Therapy.

Elamin, Ghazi / Aljoundi, Aimen / Soliman, Mahmoud E S

The protein journal

2022 Volume 41, Issue 2, Page(s) 201–215

Abstract: B-cell lymphoma 2 (Bcl2) is a key protein regulator of apoptosis. The hydrophobic groove in Bcl2 is a unique structural feature to this class of enzymes and found to have a profound impact on protein overall structure, function, and dynamics. Dynamics of ...

Abstract	B-cell lymphoma 2 (Bcl2) is a key protein regulator of apoptosis. The hydrophobic groove in Bcl2 is a unique structural feature to this class of enzymes and found to have a profound impact on protein overall structure, function, and dynamics. Dynamics of the hydrophobic groove is an essential determinant of the catalytic activity of Bcl2, an implicated protein in Waldenström macroglobulinemia (WM). The mobility of α3-α4 helices around the catalytic site of the protein remains crucial to its activity. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. In addition to our previous report on the same protein, herein, we further investigate the preferential binding modes and the conformational implications of Venetoclax-JQ1 dual drug binding at both catalytic active sites of Bcl2. Structural analysis revealed asymmetric α3-α4 helices movement with the expansion of the distance between the α3 and α4 helix in Venetoclax-JQ1 dual inhibition by 15.2% and 26.3%, respectively when compared to JQ1 and Venetoclax individual drug inhibition-resulting in remarkable widening of hydrophobic groove. Moreso, a reciprocal enhanced binding effect was observed: Venetoclax increased the binding affinity of JQ1 by 11.5%, while the JQ1 fostered the binding affinity of Venetoclax by 16.3% compared with individual inhibition of each drug. This divergence has also resulted in higher protein stability, and prominent correlated motions were observed with the least fluctuations and multiple van der Waals interactions. Findings offer vital conformational dynamics and structural mechanisms of enzyme-single ligand and enzyme-dual ligand interactions, which could potentially shift the current therapeutic protocol of Waldenström macroglobulinemia.
MeSH term(s)	Apoptosis ; Catalytic Domain ; Humans ; Ligands ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Waldenstrom Macroglobulinemia/drug therapy ; Waldenstrom Macroglobulinemia/metabolism ; Waldenstrom Macroglobulinemia/pathology
Chemical Substances	BCL2 protein, human ; Ligands ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2022-03-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2143071-8
ISSN	1875-8355 ; 1572-3887
ISSN (online)	1875-8355
ISSN	1572-3887
DOI	10.1007/s10930-022-10046-9
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Article ; Online: Inside the cracked kernel: establishing the molecular basis of AMG510 and MRTX849 in destabilising KRASG12C mutant switch I and II in cancer treatment.

Issahaku, Abdul Rashid / Salifu, Elliasu Y / Soliman, Mahmoud E S

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 11, Page(s) 4890–4902

Abstract: The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent ... ...

Abstract	The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the 'undruggable' list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRAS
MeSH term(s)	Proto-Oncogene Proteins p21(ras)/genetics ; Piperazines ; Pyridines/therapeutic use ; Fungal Proteins/genetics ; Mutation ; Neoplasms/drug therapy
Chemical Substances	adagrasib (8EOO6HQF8Y) ; sotorasib (2B2VM6UC8G) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Piperazines ; Pyridines ; Fungal Proteins
Language	English
Publishing date	2022-05-11
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2074141
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Zs.A 2093: Show issues

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Article ; Online: Investigating the Impact of Covalent and Non-covalent Binding Modes of Inhibitors on Bruton's Tyrosine Kinase in the Treatment of B Cell Malignancies - Computational Insights.

Issahaku, Abdul Rashid / Soliman, Mahmoud E S

Current pharmaceutical biotechnology

2022 Volume 24, Issue 6, Page(s) 814–824

Abstract: Background: Bruton tyrosine kinase plays a key role in the survival, proliferation, activation, and differentiation of B-lineage cells and the signaling of other receptors. It is overexpressed and constitutively active in the pathogenesis of B cell ... ...

Abstract	Background: Bruton tyrosine kinase plays a key role in the survival, proliferation, activation, and differentiation of B-lineage cells and the signaling of other receptors. It is overexpressed and constitutively active in the pathogenesis of B cell malignancies and has therefore become a target for therapeutic intervention. Some success has been achieved in the discovery of small molecules, especially in the development of irreversible inhibitors. However, these inhibitors are punctuated by off target effects and have also become less effective in patients with mutations at Cys481. This motivated the search for inhibitors with improved efficacy and different binding modes. Methods: In this study, we employed two new second generation inhibitors with different binding modes, Zanubrutinib and AS-1763, which are at various levels of clinical trials, to highlight the molecular determinants in the therapeutic inhibition of BTK through computational studies. Results: This study revealed that Zanubrutinib and AS-1763 exhibited free total binding energies of -98.76 ± 4.63 kcal/mol and -51.81 ± 9.94 kcal/mol, respectively, with Zanubrutinib engaging in peculiar hydrogen bond interactions with the hinge residues Glu475 and Met477 including Asn484 and Tyr485 while AS-1763 engaged Lys430, Asp539, and Arg525. These residues contributed the most towards the free total binding energy with energies above -1.0 kcal/mol. The compounds further interacted differentially with other binding site residues through pi-alkyl, pi-cation, pianion, pi-pi-T-shaped, pi-sigma, pi-sulfur and pi-donor hydrogen bonds, and Van der Waals interactions. These interactions resulted in differential fluctuations of the residues with the consequential unfolding of the protein. Conclusion: Insights herein would be useful in guiding the discovery of more selective and potent small molecules.
MeSH term(s)	Humans ; Agammaglobulinaemia Tyrosine Kinase/genetics ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction ; Neoplasms/drug therapy ; Cell Differentiation
Chemical Substances	Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; Protein Kinase Inhibitors
Language	English
Publishing date	2022-06-11
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/1389201023666220617151552
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Article ; Online: Co-Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenström Macroglobulinemia Lymphoma.

Elamin, Ghazi / Aljoundi, Aimen / Soliman, Mahmoud E S

Chemistry & biodiversity

2022 Volume 19, Issue 7, Page(s) e202100845

Abstract: In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual- ...

Abstract	In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual-site'-binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co-binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed - Venetoclax increased the binding affinity of JQ1 by 11.5 %, while JQ1 boosted the binding affinity of Venetoclax by 16.3 % when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Azepines/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Humans ; Lymphoma/drug therapy ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides/pharmacology ; Triazoles/pharmacology ; Waldenstrom Macroglobulinemia/drug therapy ; Waldenstrom Macroglobulinemia/metabolism ; Waldenstrom Macroglobulinemia/pathology
Chemical Substances	(+)-JQ1 compound ; Antineoplastic Agents ; Azepines ; Bridged Bicyclo Compounds, Heterocyclic ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; Triazoles ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2022-06-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2139001-0
ISSN	1612-1880 ; 1612-1872
ISSN (online)	1612-1880
ISSN	1612-1872
DOI	10.1002/cbdv.202100845
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Article ; Online: Deciphering the molecular mechanisms of selective non-covalency demonstrated differentially by 9-Allylnaphtho[1,8-ef]isoindole-7,8,10(9H)-trione (C11) against fibroblast growth factor receptors 1-4.

Olotu, Fisayo A / Soliman, Mahmoud E S

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 6, Page(s) 2419–2430

Abstract: The specific inhibition of aberrant Fibroblast Growth Factor Receptors (FGFRs) has been identified as a feasible strategy to therapeutically ameliorate their respective carcinogenic involvements. High homology among these proteins has however limited ... ...

Abstract	The specific inhibition of aberrant Fibroblast Growth Factor Receptors (FGFRs) has been identified as a feasible strategy to therapeutically ameliorate their respective carcinogenic involvements. High homology among these proteins has however limited efforts towards the discovery of selective small-molecule compounds due to undesirable effects elicited by pan-FGFR inhibitors. A recent study showed the selective activity of a new compound
MeSH term(s)	Signal Transduction ; Receptors, Fibroblast Growth Factor/antagonists & inhibitors
Chemical Substances	Receptors, Fibroblast Growth Factor
Language	English
Publishing date	2022-02-02
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2032355
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Article ; Online: Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights.

Salifu, Elliasu Y / Rashid, Issahaku A / Soliman, Mahmoud E S

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 10, Page(s) 4735–4743

Abstract: Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Available treatment options for ALK-positive NSCLCs ... ...

Abstract	Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Available treatment options for ALK-positive NSCLCs involve the use of ALK tyrosine kinase inhibitors (ALK-TKIs) which have shown to be effective with a high response rate. Nonetheless, the emergence of multiple compound mutations such as I1171N + F1174I or I1171N + L1198H has been reported to cause resistance to all approved ALK-TKIs. However, the underlying molecular mechanisms surrounding the impact of these compound mutants remain poorly understood. Hence, we performed molecular dynamics simulations to characterize the structural effects and functional implications of these compound mutations. Findings revealed a destabilizing effect on ALK by mutants as compared to the wild-type ALK structure. Also, further insights revealed a lower root-mean-squared fluctuation, radius of gyration, and solvent-accessible surface area values of I1171N + F1174I and I1171N + L1198H ALK compound mutations suggesting that the mutants have a more compact structure and a smaller surface area than the wild-type protein. The mutants also distorted the activation loop residues (Tyr1278, Tyr1282, and Tyr1283) in the ALK structure, which further identify them as possible disruptors of phosphorylation. In contrast to wild conformation, the mutant conformations exhibited a reduced node degree in their residue interaction networks. Collectively, our findings provide deeper insights into the deleterious effects of I1171N + F1174I and I1171N + L1198H ALK compound mutations, which may contribute to NSCLC pathogenesis.Communicated by Ramaswamy H. Sarma.
MeSH term(s)	Humans ; Anaplastic Lymphoma Kinase/genetics ; Drug Resistance, Neoplasm/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Mutation ; Protein Kinase Inhibitors/pharmacology
Chemical Substances	Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; Protein Kinase Inhibitors
Language	English
Publishing date	2022-05-05
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2072390
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Article ; Online: The Binding of Remdesivir to SARS-CoV-2 RNA-Dependent RNA Polymerase May Pave The Way Towards the Design of Potential Drugs for COVID-19 Treatment.

Agoni, Clement / Soliman, Mahmoud E S

Current pharmaceutical biotechnology

2020 Volume 22, Issue 11, Page(s) 1520–1537

Abstract: Aim: We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties.: ...

Abstract	Aim: We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. Background: The coronavirus disease of 2019 (COVID-19) pandemic had infected over a million people, with 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline is Remdesivir. Objectives: We performed the molecular dynamics simulation, quantified the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generated a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. Methods: Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced post-molecular dynamics analysis techniques were employed. Results: Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of high-affinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms, and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the "buried" hydrophobic region to the "surface-exposed" hydrophilic region. We also mapped a pharmacophore model based on the observed high-affinity interactions with SARSCoV- 2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. Conclusion: The structural insights and the provided optimized pharmacophoric model would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Alanine/analogs & derivatives ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; Humans ; Pharmaceutical Preparations ; RNA, Viral ; RNA-Dependent RNA Polymerase/genetics ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Pharmaceutical Preparations ; RNA, Viral ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-10-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/1389201021666201027154833
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Article ; Online: Unveiling a New Era in Malaria Therapeutics: A Tailored Molecular Approach Towards the Design of Plasmepsin IX Inhibitors.

Munsamy, Geraldene / Soliman, Mahmoud E S

The protein journal

2019 Volume 38, Issue 6, Page(s) 616–627

Abstract: The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development ... ...

Abstract	The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development of effective therapeutics, factors such as emerging strains of drug resistance, enhanced toxicity and poor pharmacokinetic properties of current therapeutics has hampered the drug discovery process resulting in the spread of this parasitic disease. A promising target of the most lethal strain of the Plasmodium species that plays a predicted role in erythrocyte invasion of the virulent malarial parasite is aspartic protease IX commonly referred to Plasmepsin IX. The integration of computer aided-drug design platforms has revolutionized the 21st century and has opened avenues to render a final "knock out" in the elimination and eradication of this parasitic disease Hitherto, this is the first attempt directed towards the design of therapeutics tailored explicitly to Plasmepsin IX. A potent peptidomimetic inhibitor referred to as 49c which is a known inhibitor of Plasmepsin II, has recently exhibited potent inhibitory activity against Plasmepsin IX. In-silico structural and physicochemical inspection of 49c displayed poor pharmacokinetic properties thus paving the way for the development of tailored inhibitors with desirable therapeutic properties against Plasmepsin IX. In this study we implement the pharmacophore model approach in combination with per-residue energy decomposition analysis to serve as a powerful cornerstone, that may assist medicinal experts in the composition of multifunctional therapeutics that may predispose factors such as cross-resistance and toxicity, with enhanced pharmacokinetic properties.
MeSH term(s)	Aspartic Acid Endopeptidases/antagonists & inhibitors ; Drug Design ; Malaria/drug therapy ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Protease Inhibitors/chemistry
Chemical Substances	Protease Inhibitors ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; plasmepsin (EC 3.4.23.38)
Language	English
Publishing date	2019-10-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2143071-8
ISSN	1875-8355 ; 1572-3887
ISSN (online)	1875-8355
ISSN	1572-3887
DOI	10.1007/s10930-019-09871-2
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