Unveiling the multitargeted potential of N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) against SARS CoV-2: a virtual screening and molecular dynamics simulation study

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

doi:10.1080/07391102.2022.2110158

Cited by 23 publications

(13 citation statements)

References 30 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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“…This study aims to identify a multitargeted drug candidate that potentially can target all five proteins and have an excellent binding score and stable performance. We conducted the docking studies with HTVS, SP, and XP algorithms and filtered the docked poses with MM\GBSA [ 1 , 30 , 31 , 32 ]. Further, we have also performed the pharmacokinetics computations and molecular interactions fingerprints to understand the pattern and the MD simulation to evaluate all the results and check if the compounds are stable and can be validated experimentally in the future or not.…”

Section: Introductionmentioning

confidence: 99%

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

Hakami,

Hazazi,

Albloui

et al. 2024

IJMS

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Lung cancer is a pervasive and challenging disease with limited treatment options, with global health challenges often present with complex molecular profiles necessitating the exploration of innovative therapeutic strategies. Single-target drugs have shown limited success due to the heterogeneity of this disease. Multitargeted drug designing is imperative to combat this complexity by simultaneously targeting multiple target proteins and pathways, which can enhance treatment efficacy and overcome resistance by addressing the dynamic nature of the disease and stopping tumour growth and spread. In this study, we performed the molecular docking studies of Drug Bank compounds with a multitargeted approach against crucial proteins of lung cancer such as heat shock protein 5 (BIP/GRP78) ATPase, myosin 9B RhoGAP, EYA2 phosphatase inhibitor, RSK4 N-terminal kinase, and collapsin response mediator protein-1 (CRMP-1) using HTVS, SP with XP algorithms, and poses were filtered using MM\GBSA which identified [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BenCarMethIn YlPro-Phosphonic Acid) (DB02504) as multitargeted drug candidate with docking and MM\GBSA score ranges from −5.83 to −10.66 and −7.56 to −50.14 Kcal/mol, respectively. Further, the pharmacokinetic and QM-based DFT studies have shown complete acceptance results, and interaction fingerprinting reveals that ILE, GLY, VAL, TYR, LEU, and GLN were among the most interacting residues. The 100 ns MD simulation in the SPC water model with NPT ensemble showed stable performance with deviation and fluctuations <2 Å with huge interactions, making it a promising multitargeted drug candidate; however, experimental studies are needed before use.

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“…The leading cause of most cervical cancer cases is a long-lasting infection with high-risk strains of the human papillomavirus (HPV), mainly types 16 and 18. These two types of HPV are responsible for about 70% of all cervical cancer cases [2,3]. While implementing HPV vaccination and regular cervical screening programs has reduced cervical cancer cases in many developed countries, it remains a formidable challenge in low-resource settings where access to these preventive measures is limited.…”

Section: Introductionmentioning

confidence: 99%

“…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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Unveiling the multitargeted potential of N-(4-Aminobutanoyl)-S-(4-methoxybenzyl)-L-cysteinylglycine (NSL-CG) against SARS CoV-2: a virtual screening and molecular dynamics simulation study

Cited by 23 publications

References 30 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

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

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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