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Article: De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies.

Alzain, Abdulrahim A / Elbadwi, Fatima A

Advances and applications in bioinformatics and chemistry : AABC

2022 Volume 15, Page(s) 29–41

Abstract: Background: Schistosomiasis is the world's second most devastating disease after malaria and the leading cause of disease and mortality for more than 200 million people in developing countries. Cysteine proteases, in particular SmCB1, are the most well- ... ...

Abstract	Background: Schistosomiasis is the world's second most devastating disease after malaria and the leading cause of disease and mortality for more than 200 million people in developing countries. Cysteine proteases, in particular SmCB1, are the most well-researched biological targets for this disorder. Objective: To apply computational techniques to design new antischistosomal agents against SmCB1 protein with favorable pharmacokinetic properties. Methods: The smCB1 receptor-based pharmacophore model was created and used to screen 567,000 fragments from the Enamine library. The best scoring fragments have been linked to build novel compounds that were subjected to molecular docking, MM-GBSA free energy estimation, ADME prediction, and molecular dynamics. Results: A seven-point pharmacophore hypothesis ADDDRRR was created. The developed hypothesis was used to screen 1.3 M fragment conformations. Among them, 23,732 fragments matched the hypothesis and screened against the protein. The top 50 fragments were used to design new 7745 compounds using the Breed ligand panel which were subjected to docking and MMGBSA binding energy. This led to the identification of 10 compounds with better docking scores (-8.033- -7.483 kcal/mol) and lower-bound free energies (-58.49 - -40.02 kcal/mol) compared to the reference bound ligand. Most of the designed compounds demonstrated good drug-like properties. Concerning Molecular dynamics (MD) simulation results, a low root mean square deviation (RMSD) range (0.25-1.2 Å) was found for the top 3 complexes which indicated their stability. Conclusion: We identified compounds that could be potential candidates in the search for novel
Language	English
Publishing date	2022-08-01
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2494731-3
ISSN	1178-6949
ISSN	1178-6949
DOI	10.2147/AABC.S361626
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Article ; Online: Targeting the omicron variant of SARS-CoV-2 with phytochemicals from Saudi medicinal plants: molecular docking combined with molecular dynamics investigations.

Eltaib, Lina / Alzain, Abdulrahim A

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 19, Page(s) 9732–9744

Abstract: The new health crises caused by SARS-CoV-2 have resulted in millions of deaths worldwide. First discovered in November 2021, the omicron variant is more transmissible and is able to evade the immune system better than other previously identified SARS-CoV- ...

Abstract	The new health crises caused by SARS-CoV-2 have resulted in millions of deaths worldwide. First discovered in November 2021, the omicron variant is more transmissible and is able to evade the immune system better than other previously identified SARS-CoV-2 variants, leading to a spike in cases. Great efforts have been made to discover inhibitors against SARS-CoV-2. Main protease (M
MeSH term(s)	Molecular Docking Simulation ; COVID-19 ; Molecular Dynamics Simulation ; Plants, Medicinal ; SARS-CoV-2 ; Saudi Arabia ; Phytochemicals/pharmacology ; Protease Inhibitors/pharmacology
Chemical Substances	Phytochemicals ; Protease Inhibitors
Language	English
Publishing date	2022-11-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2146203
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Article ; Online: Cytosporone E analogues as BRD4 inhibitors for cancer treatment: molecular docking and molecular dynamic investigations.

Makki, Alaa A / Ibraheem, Walaa / Alzain, Abdulrahim A

Journal of biomolecular structure & dynamics

2023 Volume 41, Issue 22, Page(s) 12643–12653

Abstract: Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel ... ...

Abstract	Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel anticancer agents. Bromodomains have a vital role in the regulation of transcription. Many reports have shown that bromodomain-containing protein 4 (BRD4) is an important target for cancer therapeutics. In this study, several
MeSH term(s)	Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Transcription Factors/chemistry ; Nuclear Proteins/chemistry ; Binding Sites ; Ligands ; Protein Binding ; Neoplasms ; Cell Cycle Proteins/metabolism
Chemical Substances	Transcription Factors ; Nuclear Proteins ; cytosporone E ; Ligands ; BRD4 protein, human ; Cell Cycle Proteins
Language	English
Publishing date	2023-01-16
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2023.2167122
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Article: Identification of novel TMPRSS2 inhibitors for COVID-19 using e-pharmacophore modelling, molecular docking, molecular dynamics and quantum mechanics studies.

Alzain, Abdulrahim A / Elbadwi, Fatima A

Informatics in medicine unlocked

2021 Volume 26, Page(s) 100758

Abstract: SARS coronavirus 2 (SARS-CoV-2) has spread rapidly around the world and continues to have a massive global health effect, contributing to an infectious respiratory illness called coronavirus infection-19 (COVID-19). TMPRSS2 is an emerging molecular ... ...

Abstract	SARS coronavirus 2 (SARS-CoV-2) has spread rapidly around the world and continues to have a massive global health effect, contributing to an infectious respiratory illness called coronavirus infection-19 (COVID-19). TMPRSS2 is an emerging molecular target that plays a role in the early stages of SARS-CoV-2 infection; hence, inhibiting its activity might be a target for COVID-19. This study aims to use many computational approaches to provide compounds that could be optimized into clinical candidates. As there is no experimentally derived protein information, initially we develop the TMPRSS2 model. Then, we generate a pharmacophore model from TMPRSS2 active site consequently, and the developed models were employed for the screening of one million molecules from the Enamine database. The created model was then screened using e-pharmacophore-based screening, molecular docking, free energy estimation and molecular dynamic simulation. Also, ADMET prediction and density functional theory calculations were performed. Three potential molecules (Z126202570, Z46489368, and Z422255982) exhibited promising stable binding interactions with the target. In conclusion, these findings empower further
Language	English
Publishing date	2021-10-14
Publishing country	England
Document type	Journal Article
ISSN	2352-9148
ISSN	2352-9148
DOI	10.1016/j.imu.2021.100758
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Article ; Online: Repurposing of approved drugs for targeting CDK4/6 and aromatase protein using molecular docking and molecular dynamics studies.

Yousif, Fatima A / Alzain, Abdulrahim A / Alraih, Alhafez M / Ibraheem, Walaa

PloS one

2023 Volume 18, Issue 9, Page(s) e0291256

Abstract: Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin ...

Abstract	Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin D1, which in turn promotes the activity of CDK4/6 and facilitates cell cycle progression. To address this, the first-line treatment for ER+ breast cancer focuses on inhibiting estrogen production by targeting aromatase, the enzyme responsible for the rate-limiting step in estrogen synthesis. Thus, combining CDK4/6 inhibitors with aromatase inhibitors has emerged as a crucial treatment strategy for this type of breast cancer. This approach effectively suppresses estrogen biosynthesis and controls uncontrolled cell proliferation, significantly improving overall survival rates and delayed disease progression. This study aimed to identify compounds that are likely to inhibit CDK4/6 and aromatase simultaneously by using a structure-based drug design strategy. 12,432 approved and investigational drugs were prepared and docked into the active site of CDK6 using HTVS and XP docking modes of Glide resulting in 277 compounds with docking scores ≤ -7 kcal/mol. These compounds were docked into aromatase enzyme using XP mode to give seven drugs with docking scores≤ -6.001 kcal/mol. Furthermore, the shortlisted drugs were docked against CDK4 showing docking scores ranging from -3.254 to -8.254 kcal/mol. Moreover, MM-GBSA for the top seven drugs was calculated. Four drugs, namely ellagic acid, carazolol, dantron, and apomorphine, demonstrated good binding affinity to all three protein targets CDK4/6 and aromatase. Specifically, they exhibited favourable binding free energy with CDK6, with values of -51.92, -53.90, -50.22, and -60.97 kcal/mol, respectively. Among these drugs, apomorphine displayed the most favourable binding free energy with all three protein targets. To further evaluate the stability of the interaction, apomorphine was subjected to a 100 ns molecular dynamics simulation with CDK6. The results indicated the formation of a stable ligand-protein complex. While the results obtained from the MM-GBSA calculation of the binding free energies of the MD conformations of apomorphine showed less favourable binding free energy compared to that obtained post-docking. All these computational findings will provide better structural insight for the development of CDK4/6 and aromatase multi-target inhibitors.
MeSH term(s)	Female ; Humans ; Molecular Docking Simulation ; Aromatase ; Molecular Dynamics Simulation ; Apomorphine ; Drug Repositioning ; Breast Neoplasms ; Estrogens ; Aromatase Inhibitors/pharmacology ; Cyclin-Dependent Kinase 4
Chemical Substances	Aromatase (EC 1.14.14.1) ; Apomorphine (N21FAR7B4S) ; Estrogens ; Aromatase Inhibitors ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2023-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0291256
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Article: Discovery of novel TMPRSS2 inhibitors for COVID-19 using

Alzain, Abdulrahim A / Elbadwi, Fatima A / Alsamani, Fatima O

Informatics in medicine unlocked

2022 Volume 29, Page(s) 100870

Abstract: The global expansion of COVID-19 and the mutations of severe acute respiratory syndrome coronavirus necessitate quick development of treatment and vaccination. Because the androgen-responsive serine protease TMPRSS2 is involved in cleaving the SARS-CoV-2 ...

Abstract	The global expansion of COVID-19 and the mutations of severe acute respiratory syndrome coronavirus necessitate quick development of treatment and vaccination. Because the androgen-responsive serine protease TMPRSS2 is involved in cleaving the SARS-CoV-2 spike protein allowing the virus to enter the cell, therefore, direct TMPRSS2 inhibition will inhibit virus activation and disease progression which make it an important target for drug discovery. In this study, a homology model of TMPRSS2 protein was initially developed. Then, we used the fragment-based drug design (FBDD) technique to develop effective TMPRSS2 inhibitors. Over a half-million fragments from the enamine database were screened for their binding ability to target protein, and then best-scoring fragments were linked to building new molecules with a good binding affinity. XP docking and MM-GBSA studies revealed 10 new formed molecules with docking score ≤ -14.982 kcal/mol compared to ambroxol (control) with a docking score of -6.464 kcal/mol. Finally, molecular dynamics (MD) and density functional theory (DFT) were calculated for the top 3 molecules.
Language	English
Publishing date	2022-02-02
Publishing country	England
Document type	Journal Article
ISSN	2352-9148
ISSN	2352-9148
DOI	10.1016/j.imu.2022.100870
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Article: Drug repurposing against main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular docking, MM-GBSA calculations and molecular dynamics.

Mohammed, Ahmed O / Abo-Idrees, Mazin I / Makki, Alaa A / Ibraheem, Walaa / Alzain, Abdulrahim A

Structural chemistry

2022 Volume 33, Issue 5, Page(s) 1553–1567

Abstract: A virus called severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) is the causing organism of coronavirus disease 2019 (COVID-19), which has severely affected human life and threatened public health. The pandemic took millions of ... ...

Abstract	A virus called severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) is the causing organism of coronavirus disease 2019 (COVID-19), which has severely affected human life and threatened public health. The pandemic took millions of lives worldwide and caused serious negative effects on human society and the economy. SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) are interesting targets due to their crucial role in viral replication and growth. Since there is only one approved therapy for COVID-19, drug repurposing is a promising approach to finding molecules with potential activity against COVID-19 in a short time and at minimal cost. In this study, virtual screening was performed on the ChEMBL library containing 9923 FDA-approved drugs, using various docking filters with different accuracy. The best drugs with the highest docking scores were further examined for molecular dynamics (MD) studies and MM-GBSA calculations. The results of this study suggest that nadide, cangrelor and denufosol are promising potential candidates against COVID-19. Further in vitro, preclinical and clinical studies of these candidates would help to discover safe and effective anti-COVID-19 drugs.
Language	English
Publishing date	2022-06-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2018832-8
ISSN	1572-9001 ; 1040-0400
ISSN (online)	1572-9001
ISSN	1040-0400
DOI	10.1007/s11224-022-01999-9
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Article ; Online: Phytochemical constituents,

Hago, Salma / Lu, Tang / Alzain, Abdulrahim A / Abdelgadir, Abdelgadir A / Yassin, Sitelbanat / Ahmed, Elhadi M / Xu, Hanmei

Natural product research

2023 Volume 38, Issue 6, Page(s) 1073–1079

Abstract: The cytotoxic effects ... ...

Abstract	The cytotoxic effects of
MeSH term(s)	Cymbopogon ; Molecular Docking Simulation ; Cell Line ; Ethanol ; Phytochemicals ; Plant Extracts/pharmacology
Chemical Substances	Ethanol (3K9958V90M) ; Phytochemicals ; Plant Extracts
Language	English
Publishing date	2023-05-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2185747-7
ISSN	1478-6427 ; 1478-6419
ISSN (online)	1478-6427
ISSN	1478-6419
DOI	10.1080/14786419.2023.2208360
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Article: Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies.

Alzain, Abdulrahim A / Elbadwi, Fatima A / Shoaib, Tagyedeen H / Sherif, Asmaa E / Osman, Wadah / Ashour, Ahmed / Mohamed, Gamal A / Ibrahim, Sabrin R M / Roh, Eun Joo / Hassan, Ahmed H E

Frontiers in chemistry

2024 Volume 12, Page(s) 1339891

Abstract: Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its ... ...

Abstract	Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of -9.891, -7.579 and -7.097 kcal/mol, respectively than the reference compound (-6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (-57.12, -49.81 and -46.05 kcal/mol, respectively) than the reference ligand (-37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer.
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2024.1339891
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Article: Assessing the antibacterial potential of 6-gingerol: Combined experimental and computational approaches.

Elfaky, Mahmoud A / Okairy, Hassan M / Abdallah, Hossam M / Koshak, Abdulrahman E / Mohamed, Gamal A / Ibrahim, Sabrin R M / Alzain, Abdulrahim A / Hegazy, Wael A H / Khafagy, El-Sayed / Seleem, Noura M

Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society

2024 Volume 32, Issue 5, Page(s) 102041

Abstract: The rise of antibiotic resistance in bacteria is becoming a global concern, particularly due to the dwindling supply of new antibiotics. This situation mandates the discovery of new antimicrobial candidates. Plant-derived natural compounds have ... ...

Abstract	The rise of antibiotic resistance in bacteria is becoming a global concern, particularly due to the dwindling supply of new antibiotics. This situation mandates the discovery of new antimicrobial candidates. Plant-derived natural compounds have historically played a crucial role in the development of antibiotics, serving as a rich source of substances possessing antimicrobial properties. Numerous studies have supported the reputation of 6-gingerol, a prominent compound found in the ginger family, for its antibacterial properties. In this study, the antibacterial activities of 6-gingerol were evaluated against Gram-negative bacteria,
Language	English
Publishing date	2024-03-18
Publishing country	Saudi Arabia
Document type	Journal Article
ZDB-ID	1378024-4
ISSN	1319-0164
ISSN	1319-0164
DOI	10.1016/j.jsps.2024.102041
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