In-Silico Screening and Molecular Dynamics Simulation of Drug Bank Experimental Compounds against SARS-CoV-2

Alturki, Norah A.; Mashraqi, Mutaib M.; Alzamami, Ahmad; Alghamdi, Youssef Saeed; Alharthi, Afaf; Asiri, Saeed Ahmed; Ahmad, Shaban; Alshamrani, Saleh

doi:10.3390/molecules27144391

Cited by 36 publications

(12 citation statements)

References 28 publications

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“…Within XP, we generated a maximum of four poses per compound and directed 100% of the XP computations to molecular mechanics with generalised born and surface area solution (MM/GBSA) analyses. This sequential approach aimed to streamline the screening process, focusing computational resources on the most promising candidates for in-depth analysis [ 37 , 49 , 50 , 51 , 52 , 53 , 54 ]. After the computations, each incorporated result was subjected to exportation to CSV in order to analyse it further and identify which drug interacts at what frequency.…”

Section: Methodsmentioning

confidence: 99%

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor

Almasoudi,

Mashraqi,

Alshamrani

et al. 2024

Pharmaceuticals

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Breast cancer begins in the breast cells, mainly impacting women. It starts in the cells that line the milk ducts or lobules responsible for producing milk and can spread to nearby tissues and other body parts. In 2020, around 2.3 million women across the globe received a diagnosis, with an estimated 685,000 deaths. Additionally, 7.8 million women were living with breast cancer, making it the fifth leading cause of cancer-related deaths among women. The mutational changes, overexpression of drug efflux pumps, activation of alternative signalling pathways, tumour microenvironment, and cancer stem cells are causing higher levels of drug resistance, and one of the major solutions is to identify multitargeted drugs. In our research, we conducted a comprehensive screening using HTVS, SP, and XP, followed by an MM/GBSA computation of human-approved drugs targeting HER2/neu, BRCA1, PIK3CA, and ESR1. Our analysis pinpointed IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor for these proteins, revealing docking scores ranging from −4.527 to −8.809 Kcal/mol and MM/GBSA scores between −49.09 and −61.74 Kcal/mol. We selected interacting residues as fingerprints, pinpointing 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU as the most prevalent in interactions. Subsequently, we analysed the ADMET properties and compared them with the standard values of QikProp. We extended our study for DFT computations with Jaguar and plotted the electrostatic potential, HOMO and LUMO regions, and electron density, followed by a molecular dynamics simulation for 100 ns in water, showing an utterly stable performance, making it a suitable drug candidate. IRESSA is FDA-approved for lung cancer, which shares some pathways with breast cancers, clearing the hurdles of multitargeted drugs against breast and lung cancer. This has the potential to be groundbreaking; however, more studies are needed to concreate IRESSA’s role.

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Section: Methodsmentioning

confidence: 99%

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor

Almasoudi,

Mashraqi,

Alshamrani

et al. 2024

Pharmaceuticals

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“…Complex structure of squalene monooxygenase and ligand was tested for stability by Molecular Dynamics (MD) simulation method for 10 ns using Desmond component, Schrödinger [25].…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Evaluation of Compounds from Balanites aegyptiaca against Squalene Epoxidase of Micropsorum gypseum—In Vitro and In Silico Studies

Abuthakir,

Hemamalini,

Alahmadi

et al. 2023

Microbiology Research

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Microsporum gypseum is a dermatophyte with a geophilic nature that is found all over the globe. It mainly causes tinea in the scalp, arms, and legs in humans. Squalene epoxidase (SE) is a crucial enzyme in M. gypseum for the biosynthesis of ergosterol. The medicinal plant Balanites aegyptiaca is an abundant supply of secondary constituents with great therapeutic values. In this research, the fruit epicarp portion was used to inhibit M. gypseum using experimental and computational techniques. The anti-dermatophytic activity of epicarp extracts on M. gypseum was evaluated using the poison plate method at five different concentrations. At 3 mg/mL, the M. gypseum was completely controlled by the fractioned chloroform extract of epicarp. The compounds from previous research were utilized for docking studies (Abuthakir et al., 2022). The ideal compounds and the drug terbinafine were then docked using Schrödinger’s Glide module. It demonstrates that (3E)-7-Hydroxy-3,7-dimethyl-3-octen-1-yl-6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside outperforms other substances and the drug terbinafine in docking analysis. Desmond, Schrödinger Molecular Dynamics simulations were also performed for (3E)-7-Hydroxy-3,7-dimethyl-3-octen-1-yl-6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside-squalene epoxidase complexes. The complex appears to be more stable, according to the MD simulation research. This study indicates that (3E)-7-Hydroxy-3,7-dimethyl-3-octen-1-yl-6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside could be used as a potential inhibitor of M. gypseum growth, and it could be studied further.

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“…Cervical cancer is a significant global health concern, and the development of effective multitargeted therapies is essential to improve patient outcomes and reduce the burden of this disease [17][18][19]. Proteins associated with cancer and cell cycle regulation in this study hold great promise as potential therapeutic targets for cervical cancer treatment [1, [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: A multitargeted docking-based MM\GBSA and MD Simulation Study

Alshehri,

Asiri,

Alzahrani

et al. 2023

Preprint

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Cervical cancer remains a significant global health concern that starts in the cervix, the lower part of the uterus that connects to the vagina and is caused by the human papillomavirus (HPV), necessitating the development of effective multitargeted effective and resistance-proof therapies. In early-stage cervical cancer may not show any symptoms, however, as the cancer progresses, some people may experience- abnormal vaginal bleeding, watery or bloody vaginal discharge, pain in the pelvis or lower back, pain during sex, and frequent and painful urination. In this study, we screened the complete FDA-approved drug library using a multitargeted inhibitory approach against four cervical cancer proteins, namely mitotic arrest deficient-2, DNA polymerase epsilon B-subunit, benzimidazole-related-1, and threonine-protein kinase-1 which crucially plays its role for the in its development process. We employed the HTVS, SP and XP algorithms for efficient filtering and screening that helped to identify Mitoxantrone 2HCl against all of them with docking and MM\GBSA scores ranging from -11.63 to -7.802 Kcal/mol and -74.38 to -47.73 Kcal/mol, respectively. We also evaluated the interaction patterns of each complex and the pharmacokinetics properties that helped gain insight into interactions. Subsequently, we performed multiscale MD simulations for 100ns to understand the dynamic behaviour and stability of the Mitoxantrone 2HCl -protein complexes that revealed the formation of stable drug-protein complexes and provided insights into the molecular interactions that contribute to Mitoxantrone’s inhibitory effects on these proteins and can be a better drug for cervical cancer. However, experimental studies of these findings could pave the way for therapies to combat cervical cancer effectively.

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In-Silico Screening and Molecular Dynamics Simulation of Drug Bank Experimental Compounds against SARS-CoV-2

Cited by 36 publications

References 28 publications

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor

Evaluation of Compounds from Balanites aegyptiaca against Squalene Epoxidase of Micropsorum gypseum—In Vitro and In Silico Studies

Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: A multitargeted docking-based MM\GBSA and MD Simulation Study

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