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Article ; Online: Taming the cytokine storm: small molecule inhibitors targeting IL-6/IL-6α receptor.

Zia, Komal / Nur-E-Alam, Mohammad / Ahmad, Aftab / Ul-Haq, Zaheer

2024

Abstract: Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the ... ...

Abstract	Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19. Given the pivotal role of IL-6 cytokine in initiating CRS, it has been considered a most potential therapeutic target to mitigate hyperactivated immune responses. While monoclonal antibodies of IL-6 show promise in mitigating cytokine storm, concerns about immunotoxicity persist, and small molecule IL-6 antagonists remain unavailable. The present study employed sophisticated computational techniques to identify potential hit compounds as IL-6 inhibitors, with the aim of inhibiting IL-6/IL-6R protein-protein interactions. Through ligand-based pharmacophore mapping and shape similarity in combination with docking-based screening, we identified nine hit compounds with diverse chemical scaffolds as potential binders of IL-6. Further, the MD simulation of 300 ns of five virtual hits in a complex with IL-6 was employed to study the dynamic behavior. To provide a more precise prediction, binding free energy was also estimated. The identified compounds persistently interacted with the residues lining the binding site of the IL-6 protein. These compounds displayed low binding energy during MMPBSA calculations, substantiating their strong association with IL-6. This study suggests promising scaffolds as potential inhibitors of IL-6/IL-6R protein-protein interactions and provides direction for lead optimization.
Language	English
Publishing date	2024-02-17
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1376507-3
ISSN	1573-501X ; 1381-1991
ISSN (online)	1573-501X
ISSN	1381-1991
DOI	10.1007/s11030-023-10805-5
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Article ; Online: Epigenetic modulation by targeting bromodomain containing protein 9 (BRD9): Its therapeutic potential and selective inhibition

Ali, Maria Mushtaq / Naz, Sehrish / Ashraf, Sajda / Knapp, Stefan / Ul-Haq, Zaheer

International Journal of Biological Macromolecules. 2023 Mar., v. 230 p.123428-

2023

Abstract: The bromodomain-containing protein 9, a component of the SWI/SNF chromatin remodeling complex, functions as an ‘epigenetic reader’ selectively recognizing acetyl-lysine marks. It regulates chromatin structure and gene expression by recruitment of ... ...

Abstract	The bromodomain-containing protein 9, a component of the SWI/SNF chromatin remodeling complex, functions as an ‘epigenetic reader’ selectively recognizing acetyl-lysine marks. It regulates chromatin structure and gene expression by recruitment of acetylated transcriptional regulators and by modulating the function of remodeling complexes. Recent data suggests that BRD9 plays an important role in regulating cellular growth and it has been suggested to drive progression of several malignant diseases such as cervical cancer, and acute myeloid leukemia. Its role in tumorigenesis suggests that selective BRD9 inhibitors may have therapeutic value in cancer therapy. Currently, there has been increasing interest in developing small molecules that can specifically target BRD9 or the closely related bromodomain protein BRD7. Available chemical probes will help to clarify biological functions of BRD9 and its potential for cancer therapy. Since the report of the first BRD9 inhibitor LP99 in 2015, numerous inhibitors have been developed. In this review, we summarized the biological roles of BRD9, structural details and the progress made in the development of BRD9 inhibitors.
Keywords	cancer therapy ; carcinogenesis ; cell growth ; chromatin ; epigenetics ; gene expression ; myeloid leukemia ; transcription (genetics) ; uterine cervical neoplasms ; BRD9 inhibitors ; Cancer ; Bromodomain protein
Language	English
Dates of publication	2023-03
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2023.123428
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Article ; Online: A deep learning-based theoretical protocol to identify potentially isoform-selective PI3Kα inhibitors.

Shafiq, Muhammad / Sherwani, Zaid Anis / Mushtaq, Mamona / Nur-E-Alam, Mohammad / Ahmad, Aftab / Ul-Haq, Zaheer

Molecular diversity

2024

Abstract: Phosphoinositide 3-kinase alpha (PI3Kα) is one of the most frequently dysregulated kinases known for their pivotal role in many oncogenic diseases. While the side effects linked to existing drugs against PI3Kα-induced cancers provide an avenue for ... ...

Abstract	Phosphoinositide 3-kinase alpha (PI3Kα) is one of the most frequently dysregulated kinases known for their pivotal role in many oncogenic diseases. While the side effects linked to existing drugs against PI3Kα-induced cancers provide an avenue for further research, the significant structural conservation among PI3Ks makes it extremely difficult to develop new isoform-selective PI3Kα inhibitors. Embracing this challenge, we herein designed a hybrid protocol by integrating machine learning (ML) with in silico drug-designing strategies. A deep learning classification model was developed and trained on the physicochemical descriptors data of known PI3Kα inhibitors and used as a screening filter for a database of small molecules. This approach led us to the prediction of 662 compounds showcasing appropriate features to be considered as PI3Kα inhibitors. Subsequently, a multiphase molecular docking was applied to further characterize the predicted hits in terms of their binding affinities and binding modes in the targeted cavity of the PI3Kα. As a result, a total of 12 compounds were identified whereas the best poses highlighted the efficiency of these ligands in maintaining interactions with the crucial residues of the protein to be targeted for the inhibition of associated activity. Notably, potential activity of compound 12 in counteracting PI3Kα function was found in a previous in vitro study. Following the drug-likeness and pharmacokinetic characterizations, six compounds (compounds 1, 2, 3, 6, 7, and 11) with suitable ADME-T profiles and promising bioavailability were selected. The mechanistic studies in dynamic mode further endorsed the potential of identified hits in blocking the ATP-binding site of the receptor with higher binding affinities than the native inhibitor, alpelisib (BYL-719), particularly the compounds 1, 2, and 11. These outcomes support the reliability of the developed classification model and the devised computational strategy for identifying new isoform-selective drug candidates for PI3Kα inhibition.
Language	English
Publishing date	2024-02-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1376507-3
ISSN	1573-501X ; 1381-1991
ISSN (online)	1573-501X
ISSN	1381-1991
DOI	10.1007/s11030-023-10799-0
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Article ; Online: Indenoquinoxaline-phenylacrylohydrazide hybrids as promising drug candidates for the treatment of type 2 diabetes: In vitro and in silico evaluation of enzyme inhibition and antioxidant activity.

Hameed, Shehryar / Saleem, Faiza / Özil, Musa / Baltaş, Nimet / Salar, Uzma / Ashraf, Sajda / Ul-Haq, Zaheer / Taha, Muhammad / Khan, Khalid Mohammed

International journal of biological macromolecules

2024 Volume 263, Issue Pt 2, Page(s) 129517

Abstract: Existing drugs that are being used to treat type-2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been ... ...

Abstract	Existing drugs that are being used to treat type-2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been explored as antidiabetic agents. In this study, a series of new indenoquinoxaline-phenylacrylohydrazide hybrids (1-30) were synthesized, structurally characterized, and evaluated for α-amylase and α-glucosidase inhibitory activities, as well as for their antioxidant properties. All scaffolds exhibited varying degrees of inhibitory activity against both enzymes, with IC
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2/drug therapy ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; alpha-Glucosidases/metabolism ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Glycoside Hydrolase Inhibitors/pharmacology ; Glycoside Hydrolase Inhibitors/therapeutic use ; alpha-Amylases/metabolism ; Molecular Docking Simulation ; Structure-Activity Relationship
Chemical Substances	Antioxidants ; alpha-Glucosidases (EC 3.2.1.20) ; Hypoglycemic Agents ; Glycoside Hydrolase Inhibitors ; alpha-Amylases (EC 3.2.1.1)
Language	English
Publishing date	2024-01-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2024.129517
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Article ; Online: Predicting FFAR4 agonists using structure-based machine learning approach based on molecular fingerprints.

Sherwani, Zaid Anis / Tariq, Syeda Sumayya / Mushtaq, Mamona / Siddiqui, Ali Raza / Nur-E-Alam, Mohammad / Ahmed, Aftab / Ul-Haq, Zaheer

Scientific reports

2024 Volume 14, Issue 1, Page(s) 9398

Abstract: Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating ... ...

Abstract	Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4. Molecular structures were encoded into bit arrays, serving as molecular fingerprints, which were subsequently analyzed using the Bayesian network algorithm to identify patterns for screening the data. The shortlisted hits obtained via machine learning protocols were further validated by Molecular Docking and via ADME and Toxicity predictions. The shortlisted compounds were then subjected to MD Simulations of the membrane-bound FFAR4-ligand complexes for 100 ns each. Molecular analyses, encompassing binding interactions, RMSD, RMSF, RoG, PCA, and FEL, were conducted to scrutinize the protein-ligand complexes at the inter-atomic level. The analyses revealed significant interactions of the shortlisted compounds with the crucial residues of FFAR4 previously documented. FFAR4 as part of the complexes demonstrated consistent RMSDs, ranging from 3.57 to 3.64, with minimal residue fluctuations 5.27 to 6.03 nm, suggesting stable complexes. The gyration values fluctuated between 22.8 to 23.5 nm, indicating structural compactness and orderliness across the studied systems. Additionally, distinct conformational motions were observed in each complex, with energy contours shifting to broader energy basins throughout the simulation, suggesting thermodynamically stable protein-ligand complexes. The two compounds CHEMBL2012662 and CHEMBL64616 are presented as potential FFAR4 agonists, based on these insights and in-depth analyses. Collectively, these findings advance our comprehension of FFAR4's functions and mechanisms, highlighting these compounds as potential FFAR4 agonists worthy of further exploration as innovative treatments for metabolic and immune-related conditions.
MeSH term(s)	Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/metabolism ; Receptors, G-Protein-Coupled/chemistry ; Molecular Docking Simulation ; Machine Learning ; Humans ; Molecular Dynamics Simulation ; Ligands ; Protein Binding ; Bayes Theorem ; Binding Sites
Chemical Substances	Receptors, G-Protein-Coupled ; FFAR4 protein, human ; Ligands
Language	English
Publishing date	2024-04-24
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/s41598-024-60056-z
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Article ; Online: Identification of novel small molecule inhibitors for solute carrier SGLT1; a computational exploration.

Haider, Sajjad / Mushtaq, Mamona / Nur-E-Alam, Mohammad / Ahmed, Aftab / Ul-Haq, Zaheer

Journal of biomolecular structure & dynamics

2023 , Page(s) 1–11

Abstract: Diabetes results in substantial disabilities, diminished quality of life, and mortality that imposes a huge economic burden on societies and governments worldwide. Despite the absence of specific oral therapies at present, there exists an urgent ... ...

Abstract	Diabetes results in substantial disabilities, diminished quality of life, and mortality that imposes a huge economic burden on societies and governments worldwide. Despite the absence of specific oral therapies at present, there exists an urgent requirement to develop a novel drug for the treatment of diabetes mellitus. The membrane protein sodium glucose co-transporters (SGLT1) present a captivating therapeutic target for diabetes, given its pivotal role in facilitating glucose absorption in the small intestine, offering immense promise for potential therapeutic intervention. In this connection, the present study is aimed at identifying potential inhibitors of SGLT1 from a small molecule database, including compounds from both natural as well as synthetic origins. A comprehensive approach was employed, by integrating homology modeling, ligand-based pharmacophore modeling, virtual screening, and molecular docking simulation. The process resulted in the identification of 16 new compounds, featuring similar attributes as observed for the documented actives. In a systematic screening procedure, five potential virtual hits were selected for simulation studies followed by subsequent binding free energy calculations, providing deeper insight into the time-dependent behavior of protein-ligand complexes in a dynamic state. In conclusion, our findings demonstrated that the identified compounds, particularly
Language	English
Publishing date	2023-10-19
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2023.2270708
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Article ; Online: Highlights in TMPRSS2 inhibition mechanism with guanidine derivatives approved drugs for COVID-19 treatment.

Tachoua, Wafa / Kabrine, Mohamed / Mushtaq, Mamona / Selmi, Ahmed / Ul-Haq, Zaheer

Journal of biomolecular structure & dynamics

2023 Volume 41, Issue 22, Page(s) 12908–12922

Abstract: Transmembrane protease serine 2 (TMPRSS2) has been identified as a critical key for the entry of coronaviruses into human cells by cleaving and activating the spike protein of SARS-CoV-2. To block the TMPRSS2 function, 18 approved drugs, containing the ... ...

Abstract	Transmembrane protease serine 2 (TMPRSS2) has been identified as a critical key for the entry of coronaviruses into human cells by cleaving and activating the spike protein of SARS-CoV-2. To block the TMPRSS2 function, 18 approved drugs, containing the guanidine group were tested against TMPRSS2's ectodomain (7MEQ). Among these drugs, Famotidine, Argatroban, Guanadrel and Guanethidine strongly binds with TMPRSS2 S1 pocket with estimated Fullfitness energies of -1847.12, -1630.87, -1605.81 and -1600.52 kcal/mol, respectively. A significant number of non-covalent interactions such as hydrogen bonding, hydrophobic and electrostatic interactions were detected in protein-ligand complexes. In addition, the ADMET analysis revealed a perfect concurrence with the aptitude of these drugs to be developed as an anti-SARS-CoV-2 therapeutics. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior and stability of protein-ligand complexes. The results obtained herein highlight the enhanced stability and good binding affinities of the Argatroban and Famotidine towards the target protein, hence might act as new scaffolds for TMPRSS2 inhibition.Communicated by Ramaswamy H. Sarma.
MeSH term(s)	Humans ; COVID-19 ; COVID-19 Drug Treatment ; Famotidine ; Ligands ; SARS-CoV-2 ; Antihypertensive Agents ; Guanidines/pharmacology ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protease Inhibitors/pharmacology ; Serine Endopeptidases
Chemical Substances	argatroban (IY90U61Z3S) ; Famotidine (5QZO15J2Z8) ; Ligands ; Antihypertensive Agents ; Guanidines ; Protease Inhibitors ; TMPRSS2 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2023-01-29
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2023.2169762
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Article ; Online: Epigenetic modulation by targeting bromodomain containing protein 9 (BRD9): Its therapeutic potential and selective inhibition.

Ali, Maria Mushtaq / Naz, Sehrish / Ashraf, Sajda / Knapp, Stefan / Ul-Haq, Zaheer

International journal of biological macromolecules

2023 Volume 230, Page(s) 123428

Abstract: The bromodomain-containing protein 9, a component of the SWI/SNF chromatin remodeling complex, functions as an 'epigenetic reader' selectively recognizing acetyl-lysine marks. It regulates chromatin structure and gene expression by recruitment of ... ...

Abstract	The bromodomain-containing protein 9, a component of the SWI/SNF chromatin remodeling complex, functions as an 'epigenetic reader' selectively recognizing acetyl-lysine marks. It regulates chromatin structure and gene expression by recruitment of acetylated transcriptional regulators and by modulating the function of remodeling complexes. Recent data suggests that BRD9 plays an important role in regulating cellular growth and it has been suggested to drive progression of several malignant diseases such as cervical cancer, and acute myeloid leukemia. Its role in tumorigenesis suggests that selective BRD9 inhibitors may have therapeutic value in cancer therapy. Currently, there has been increasing interest in developing small molecules that can specifically target BRD9 or the closely related bromodomain protein BRD7. Available chemical probes will help to clarify biological functions of BRD9 and its potential for cancer therapy. Since the report of the first BRD9 inhibitor LP99 in 2015, numerous inhibitors have been developed. In this review, we summarized the biological roles of BRD9, structural details and the progress made in the development of BRD9 inhibitors.
MeSH term(s)	Transcription Factors/metabolism ; Protein Domains ; Cell Proliferation ; Epigenesis, Genetic
Chemical Substances	Transcription Factors
Language	English
Publishing date	2023-01-26
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2023.123428
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Article ; Online: In vitro-in silico pharmacology and chemistry of Stercularin, isolated from Sterculia diversifolia.

Ahmad, Imad / Rabbi, Fazle / Nisar, Amna / Ul-Haq, Zaheer / Khan, Alamgir

Computational biology and chemistry

2023 Volume 109, Page(s) 108008

Abstract: Stercularin is a coumarin, isolated from the ethyl acetate fraction of stem bark and leaves of S. diversifolia. Pharmacologically it is active against cancer, diabetes, and inflammation etc. The molecule is further screened for in vitro pharmacological ... ...

Abstract	Stercularin is a coumarin, isolated from the ethyl acetate fraction of stem bark and leaves of S. diversifolia. Pharmacologically it is active against cancer, diabetes, and inflammation etc. The molecule is further screened for in vitro pharmacological activities. In addition, a detailed description on its drug likeness and pharmacokinetic profile has been established to further explore its fate as a drug candidate. Stercularin exhibited antiglycation, immunomodulatory, and leishmanicidal activity in three different in vitro models. The IC
MeSH term(s)	Humans ; Sterculia ; Caco-2 Cells ; Blood-Brain Barrier
Language	English
Publishing date	2023-12-27
Publishing country	England
Document type	Journal Article
ISSN	1476-928X
ISSN (online)	1476-928X
DOI	10.1016/j.compbiolchem.2023.108008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Immunoinformatic approach for the construction of multi-epitopes vaccine against omicron COVID-19 variant

Khan, Kanwal / Khan, Salman Ali / Jalal, Khurshid / Ul-Haq, Zaheer / Uddin, Reaz

Virology. 2022 July, v. 572

2022

Abstract: The newly discovered SARS-CoV-2 Omicron variant B.1.1.529 is a Variant of Concern (VOC) announced by the World Health Organization (WHO). It's becoming increasingly difficult to keep these variants from spreading over the planet. The fifth wave has begun ...

Abstract	The newly discovered SARS-CoV-2 Omicron variant B.1.1.529 is a Variant of Concern (VOC) announced by the World Health Organization (WHO). It's becoming increasingly difficult to keep these variants from spreading over the planet. The fifth wave has begun in several countries because of Omicron variant, and it is posing a threat to human civilization. As a result, we need effective vaccination that can tackle Omicron SARS-CoV-2 variants that are bound to emerge. Therefore, the current study is an initiative to design a peptide-based chimeric vaccine that may potentially battle SARS-CoV-2 Omicron variant. As a result, the most relevant epitopes present in the mutagenic areas of Omicron spike protein were identified using a set of computational tools and immunoinformatic techniques to uncover common MHC-1, MHC-II, and B cell epitopes that may have the ability to influence the host immune mechanism. A final of three epitopes from CD8⁺ T-cell, CD4⁺ T-cell epitopes, and B-cell were shortlisted from spike protein, and that are highly antigenic, IFN-γ inducer, as well as overlapping for the construction of twelve vaccine models. As a result, the antigenic epitopes were coupled with a flexible and stable peptide linker, and the adjuvant was added at the N-terminal end to create a unique vaccine candidate. The structure of a 3D vaccine candidate was refined, and its quality was assessed by using web servers. However, the applied immunoinformatic study along with the molecular docking and simulation of 12 modeled vaccines constructs against six distinct HLAs, and TLRs (TLR2, and TLR4) complexes revealed that the V1 construct was non-allergenic, non-toxic, highly immunogenic, antigenic, and most stable. The vaccine candidate's stability was confirmed by molecular dynamics investigations. Finally, we studied the expression of the suggested vaccination using codon optimization and in-silico cloning. The current study proposed V1 Multi-Epitope Vaccine (MEV) as a significant vaccine candidate that may help the scientific community to treat SARS-CoV-2 infections.
Keywords	B-lymphocytes ; COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; World Health Organization ; adjuvants ; computer simulation ; epitopes ; humans ; immunoinformatics ; molecular dynamics ; mutagens ; peptides ; recombinant vaccines ; vaccination ; virology
Language	English
Dates of publication	2022-07
Size	p. 28-43.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2022.05.001
Database	NAL-Catalogue (AGRICOLA)

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