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Article ; Online: Dual-Target

Ramharack, Pritika / Salifu, Elliasu Y / Agoni, Clement

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: The escalating prevalence of drug-resistant strains ... ...

Abstract	The escalating prevalence of drug-resistant strains of
MeSH term(s)	Mycobacterium tuberculosis ; Folic Acid Antagonists/pharmacology ; Aspartic Acid ; Catalysis ; Folic Acid
Chemical Substances	Folic Acid Antagonists ; Aspartic Acid (30KYC7MIAI) ; Folic Acid (935E97BOY8)
Language	English
Publishing date	2023-09-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241814021
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Article ; Online: Dual-Target Mycobacterium tuberculosis Inhibition

Pritika Ramharack / Elliasu Y. Salifu / Clement Agoni

International Journal of Molecular Sciences, Vol 24, Iss 14021, p

Insights into the Molecular Mechanism of Antifolate Drugs

2023 Volume 14021

Abstract: The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential ... ...

Abstract	The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential biochemical pathways while minimizing the potential for resistance development. The concept of dual targeting has gained prominence in drug discovery against resistance bacteria. Dual targeting recognizes the complexity of cellular processes and disrupts more than one vital pathway, simultaneously. By inhibiting more than one essential process required for bacterial growth and survival, the chances of developing resistance are substantially reduced. A previously reported study investigated the dual-targeting potential of a series of novel compounds against the folate pathway in Mycobacterium tuberculosis . Expanding on this study, we investigated the predictive pharmacokinetic profiling and the structural mechanism of inhibition of UCP1172, UCP1175, and UCP1063 on key enzymes, dihydrofolate reductase (DHFR) and 5-amino-6-ribitylamino-2,4(1 H ,3 H )-pyrimidinedione 5′-phosphate reductase (RV2671), involved in the folate pathway. Our findings indicate that the compounds demonstrate lipophilic physiochemical properties that promote gastrointestinal absorption, and may also inhibit the drug-metabolizing enzyme, cytochrome P450 3A4, thus enhancing their biological half-life. Furthermore, key catalytic residues (Serine, Threonine, and Aspartate), conserved in both enzymes, were found to participate in vital molecular interactions with UCP1172, which demonstrated the most favorable free binding energies to both DHFR and RV2671 (−41.63 kcal/mol, −48.04 kcal/mol, respectively). The presence of characteristic loop shifts, which are similar in both enzymes, also indicates a common inhibitory mechanism by UCP1172. This elucidation advances the understanding of UCP1172’s dual inhibition mechanism against Mycobacterium tuberculosis.
Keywords	Mtb drug resistance ; dual-target modulation ; molecular dynamic simulations ; cheminformatics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Structural Insights into the Role of Pseudouridimycin Binding in Disruption of Bacterial RNA Polymerase Bridge Helix Conformational Arrangement.

H Rabbad, Ali / Agoni, Clement / E Soliman, Mahmoud

Current pharmaceutical biotechnology

2022 Volume 24, Issue 4, Page(s) 562–569

Abstract: Background: The bridge helix (BH) is a crucial region in bacterial RNA polymerase (RNAP) catalysis. It plays an essential role in the nucleotide addition cycle (NAC) by performing many modulated rearrangements and conformational changes. Any changes in ... ...

Abstract	Background: The bridge helix (BH) is a crucial region in bacterial RNA polymerase (RNAP) catalysis. It plays an essential role in the nucleotide addition cycle (NAC) by performing many modulated rearrangements and conformational changes. Any changes in the bridge helix conformational arrangements could perturb the NAC. Objective: Pseudouridimycin (PUM) was recently reported as a new RNAP inhibitor. However, the crucial role of the bridge helix in the inhibitory activity of PUM remains unclear, hence the aim of this study. Methods: The PUM interaction and the structural dynamics of bacterial Bridge Helix upon PUM binding were investigated using various dynamic analysis approaches. Results: Besides establishing the importance of the bridge helix residues in the binding of PUM, the findings of this study revealed that the adjacent binding of PUM induces a stabilized and structurally rigid bridge helix characterized by a reduction of individual residue flexibility, which could interfere with its role in the NAC. In addition, a hydrophobic structural rearrangement of the bridge helix is observed, evidenced by the burial and folding of residues into the hydrophobic core and a switch in the secondary structure of some regions of the bridge helix from the turn and bend to the alpha helix. The observed conformational disruption of the bridge helix upon binding of PUM also accounts for the reported inhibitory prowess and broad-spectrum activity as widely reported. Conclusion We believe findings from this study will further complement current drug discovery knowledge on disrupting bacterial RNAP machinery.
MeSH term(s)	DNA-Directed RNA Polymerases ; Nucleosides ; Bacteria/metabolism ; Protein Structure, Secondary
Chemical Substances	pseudouridimycin ; DNA-Directed RNA Polymerases (EC 2.7.7.6) ; Nucleosides
Language	English
Publishing date	2022-05-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/1389201023666220511211433
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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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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: Modelling the Transitioning of SARS-CoV-2 nsp3 and nsp4 Lumenal Regions towards a More Stable State on Complex Formation

Nele Klatte / Denis C. Shields / Clement Agoni

International Journal of Molecular Sciences, Vol 24, Iss 1, p

2022 Volume 720

Abstract: During coronavirus infection, three non-structural proteins, nsp3, nsp4, and nsp6, are of great importance as they induce the formation of double-membrane vesicles where the replication and transcription of viral gRNA takes place, and the interaction of ... ...

Abstract	During coronavirus infection, three non-structural proteins, nsp3, nsp4, and nsp6, are of great importance as they induce the formation of double-membrane vesicles where the replication and transcription of viral gRNA takes place, and the interaction of nsp3 and nsp4 lumenal regions triggers membrane pairing. However, their structural states are not well-understood. We investigated the interactions between nsp3 and nsp4 by predicting the structures of their lumenal regions individually and in complex using AlphaFold2 as implemented in ColabFold. The ColabFold prediction accuracy of the nsp3–nsp4 complex was increased compared to nsp3 alone and nsp4 alone. All cysteine residues in both lumenal regions were modelled to be involved in intramolecular disulphide bonds. A linker region in the nsp4 lumenal region emerged as crucial for the interaction, transitioning to a structured state when predicted in complex. The key interactions modelled between nsp3 and nsp4 appeared stable when the transmembrane regions of nsp3 and nsp4 were added to the modelling either alone or together. While molecular dynamics simulations (MD) demonstrated that the proposed model of the nsp3 lumenal region on its own is not stable, key interactions between nsp and nsp4 in the proposed complex model appeared stable after MD. Together, these observations suggest that the interaction is robust to different modelling conditions. Understanding the functional importance of the nsp4 linker region may have implications for the targeting of double membrane vesicle formation in controlling coronavirus infection.
Keywords	SARS-CoV-2 ; non-structural proteins ; nsp3 ; nsp4 ; transmembrane proteins ; protein-protein interaction ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Repurposing antiviral phytochemicals from the leaf extracts of Spondias mombin (Linn) towards the identification of potential SARSCOV-2 inhibitors.

Boadu, Akwasi / Agoni, Clement / Karpoormath, Rajshekhar / Soliman, Mahmoud / Nlooto, Manimbulu

Scientific reports

2022 Volume 12, Issue 1, Page(s) 10896

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pneumonia-like disease with a pattern of acute respiratory symptoms, currently remains a significant public health concern causing tremendous human suffering. Although several approved ... ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pneumonia-like disease with a pattern of acute respiratory symptoms, currently remains a significant public health concern causing tremendous human suffering. Although several approved vaccines exist, vaccine hesitancy, limited vaccine availability, high rate of viral mutation, and the absence of approved drugs account for the persistence of SARS-CoV-2 infections. The investigation of possibly repurposing of phytochemical compounds as therapeutic alternatives has gained momentum due to their reported affordability and minimal toxicity. This study investigated anti-viral phytochemical compounds from ethanolic leaf extracts of Spondias mombin L as potential inhibitor candidates against SARS-CoV-2. We identified Geraniin and 2-O-Caffeoyl-(+)-allohydroxycitric acid as potential SARS-CoV-2 inhibitor candidates targeting the SARS-CoV-2 RNA-dependent polymerase receptor-binding domain (RBD) of SARS-CoV-2 viral S-protein and the 3C-like main protease (3CL
MeSH term(s)	Anacardiaceae ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Coronavirus 3C Proteases ; Cysteine Endopeptidases/chemistry ; Drug Repositioning ; Humans ; Phytochemicals/pharmacology ; RNA, Viral ; SARS-CoV-2 ; Viral Proteins/chemistry ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Phytochemicals ; RNA, Viral ; Viral Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2022-06-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-14558-3
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Article ; Online: Dual-Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes Towards Glioma Therapy: Structural Mechanistic Insights on the Role of Vorasidenib.

Poonan, Preantha / Agoni, Clement / Soliman, Mahmoud E S

Chemistry & biodiversity

2021

Abstract: Recently, Vorasidenib (AG-881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against mIDH1/2 towards the treatment of low-grade glioma. However, structural and dynamic events associated with its dual ... ...

Abstract	Recently, Vorasidenib (AG-881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against mIDH1/2 towards the treatment of low-grade glioma. However, structural and dynamic events associated with its dual inhibition mechanism remain unclear. As such, we employ integrative computer-assisted atomistic techniques to provide thorough structural and dynamic insights. Our analysis proved that the dual-targeting ability of AG-881 is mediated by Val255/Val294 within the binding pockets of both mIDH1 and mIDH2 which are shown to elicit a strong intermolecular interaction, thus favoring binding affinity. The structural orientations of AG-881 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for its high binding free energy of -28.69 kcal/mol and -19.89 kcal/mol towards mIDH1 and mIDH2, respectively. Interestingly, upon binding, AG-881 was found to trigger systemic alterations of mIDH1 and mIDH2 characterized by restricted residue flexibility and a reduction in exposure of residues to the solvent surface area. As a result of these structural alterations, crucial interactions of the mutant enzymes were inhibited, a phenomenon that results in a suppression of the production of oncogenic stimulator 2-HG. Findings therefore provide thorough structural and dynamic insights associated with the dual inhibitory activity of AG-881 towards glioma therapy.
Language	English
Publishing date	2021-05-12
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.202100110
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Article ; Online: Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 (mIDH1) in cancer therapy

Elliasu Y. Salifu / Clement Agoni / Mahmoud E.S. Soliman

Informatics in Medicine Unlocked, Vol 28, Iss , Pp 100829- (2022)

2022

Abstract: Mutations in isocitrate dehydrogenase enzymes 1 and 2 (mIDH1/2) results in an aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), excess of which has been shown to inhibit alpha ketoglutarate (αKG)-dependent enzymes leading to the development of ... ...

Abstract	Mutations in isocitrate dehydrogenase enzymes 1 and 2 (mIDH1/2) results in an aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), excess of which has been shown to inhibit alpha ketoglutarate (αKG)-dependent enzymes leading to the development of gliomas. Inhibition of mutant IDH1 has therefore been evaluated clinically as a treatment option for gliomas. Recently, Olutasidenib (FT-2102), was discovered as a highly potent and selective inhibitor of mIDH1. However, the mechanistic activities surrounding its selective inhibitory potency remain unclear. Herein, this study provides the structural and mechanistic insights that underpin the reported selectivity of FT-2102 on mDH1 using molecular dynamic (MD) simulations and advanced post-MD analysing techniques. Findings revealed that the selectivity of FT-2102 towards mIDH1 is mediated by high-affinity interactions with residues Arg109, Ile128 and Val281 within the binding pocket. Also, a unidirectional orientation of FT-2102 within mIDH1 anchored by the high-affinity interactions accounted for its higher stability and stronger binding of −56.82 kcal/mol relative to lower binding affinity of −14.48 kcal/mol towards mIDH2. Furthermore, the binding of FT-2102 in mIDH1 conferred more stability at the binding pocket which resulted in maintenance of crucial atomic interactions as compared to mIDH2 where binding was characterized by inconsistency and loss of crucial interactions. These findings thus present a detailed insight into the selective inhibitory mechanism of FT-2102 towards mIDH1 and could aid in the design and development of novel mutant IDH inhibitors.
Keywords	Isocitrate dehydrogenase 1 and 2 ; Olutasidenib ; Molecular dynamic simulation ; Binding affinity ; Dual-inhibition ; Mutation ; Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	540
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Repurposing antiviral phytochemicals from the leaf extracts of Spondias mombin (Linn) towards the identification of potential SARSCOV-2 inhibitors

Akwasi Boadu / Clement Agoni / Rajshekhar Karpoormath / Mahmoud Soliman / Manimbulu Nlooto

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 14

Abstract: Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pneumonia-like disease with a pattern of acute respiratory symptoms, currently remains a significant public health concern causing tremendous human suffering. Although several ... ...

Abstract	Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pneumonia-like disease with a pattern of acute respiratory symptoms, currently remains a significant public health concern causing tremendous human suffering. Although several approved vaccines exist, vaccine hesitancy, limited vaccine availability, high rate of viral mutation, and the absence of approved drugs account for the persistence of SARS-CoV-2 infections. The investigation of possibly repurposing of phytochemical compounds as therapeutic alternatives has gained momentum due to their reported affordability and minimal toxicity. This study investigated anti-viral phytochemical compounds from ethanolic leaf extracts of Spondias mombin L as potential inhibitor candidates against SARS-CoV-2. We identified Geraniin and 2-O-Caffeoyl-(+)-allohydroxycitric acid as potential SARS-CoV-2 inhibitor candidates targeting the SARS-CoV-2 RNA-dependent polymerase receptor-binding domain (RBD) of SARS-CoV-2 viral S-protein and the 3C-like main protease (3CLpro). Geraniin exhibited binding free energy (ΔGbind) of − 25.87 kcal/mol and − 21.74 kcal/mol towards SARS-CoV-2 RNA-dependent polymerase and receptor-binding domain (RBD) of SARS-CoV-2 viral S-protein respectively, whereas 2-O-Caffeoyl-(+)-allohydroxycitric acid exhibited a ΔGbind of − 32 kcal/mol towards 3CLpro. Molecular Dynamics simulations indicated a possible interference to the functioning of SARS-CoV-2 targets by the two identified inhibitors. However, further in vitro and in vivo evaluation of these potential SARS-CoV-2 therapeutic inhibitor candidates is needed.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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