Anti-tubercular activity evaluation of natural compounds by targeting Mycobacterium tuberculosis resuscitation promoting factor B inhibition: An in silico study

Rabaan, Ali A.; Garout, Mohammed; Aljeldah, Mohammed; Shammari, Basim R. Al; Alawfi, Abdulsalam; Alshengeti, Amer; Najim, Mustafa A.; Alrouji, Mohammed; Almuhanna, Yasir; Alissa, Mohammed; Mashraqi, Mutaib M.; Alwashmi, Ameen S. S.; Alhajri, Mashael; Al-Ateah, Souad M.; Farahat, Ramadan Abdelmoez; Mohapatra, Ranjan K.

doi:10.1007/s11030-023-10632-8

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…The re-docking scores of our selected compounds were higher than that of the reference compound, myricetin, indicating a stronger affinity for the Marburg VP35 protein. This is in line with previous reports where re-docking was used to validate and refine the virtual screening findings [28][29][30].…”

Section: Discussionsupporting

confidence: 91%

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection

Alawam,

Alshahrani

et al. 2024

Marine Drugs

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The Marburg virus (MBV), a deadly pathogen, poses a serious threat to world health due to the lack of effective treatments, calling for an immediate search for targeted and efficient treatments. In this study, we focused on compounds originating from marine fungi in order to identify possible inhibitory compounds against the Marburg virus (MBV) VP35-RNA binding domain (VP35-RBD) using a computational approach. We started with a virtual screening procedure using the Lipinski filter as a guide. Based on their docking scores, 42 potential candidates were found. Four of these compounds—CMNPD17596, CMNPD22144, CMNPD25994, and CMNPD17598—as well as myricetin, the control compound, were chosen for re-docking analysis. Re-docking revealed that these particular compounds had a higher affinity for MBV VP35-RBD in comparison to the control. Analyzing the chemical interactions revealed unique binding properties for every compound, identified by a range of Pi–cation interactions and hydrogen bond types. We were able to learn more about the dynamic behaviors and stability of the protein–ligand complexes through a 200-nanosecond molecular dynamics simulation, as demonstrated by the compounds’ consistent RMSD and RMSF values. The multidimensional nature of the data was clarified by the application of principal component analysis, which suggested stable conformations in the complexes with little modification. Further insight into the energy profiles and stability states of these complexes was also obtained by an examination of the free energy landscape. Our findings underscore the effectiveness of computational strategies in identifying and analyzing potential inhibitors for MBV VP35-RBD, offering promising paths for further experimental investigations and possible therapeutic development against the MBV.

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Section: Discussionsupporting

confidence: 91%

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection

Alawam,

Alshahrani

et al. 2024

Marine Drugs

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“…Moreover, Glu292 is the only amino acid residue that is crucial and indispensable in the catalytic activity and is responsible for the RpfB functions ( Squeglia et al, 2013 ). Interaction with Gln310 is also significant in inhibition, as benzamidine binds to only this residue to inhibit RpfB ( Rabaan et al, 2023 ), and this study also supported these results ( Figure 1D ).…”

Section: Resultssupporting

confidence: 81%

“…It goes into reversible low metabolic dormancy, allowing it to survive for a longer period of time without dividing ( Kell and Young, 2000 ). Mtb is compromising the host’s immune defense mechanism due to its latent infections, resulting in immune system weakening ( Rabaan et al, 2023 ), and lack of symptoms. According to a WHO study (2018) on the latent TB infection, Mtb affects over a third of the world’s population ( WHO, 2021a ), causing two million deaths annually ( Corbett et al, 2003 ), mainly due to its dormancy and propensity to spread infection during this period ( WHO, 2021a ).…”

Section: Introductionmentioning

confidence: 99%

“…The increasing multi-drug resistance due to latent infections poses a life-threatening challenge, as current treatments such as isoniazid, rifampicin, ethambutol, and pyrazinamide are effective only for drug-susceptible TB ( WHO, 2021b ) and are inadequate for its multidrug-resistant, extensively drug-resistant, and totally drug-resistant strains ( CDC, 2020 ; Rabaan et al, 2023 ). Hence, there exists an urgent necessity to comprehensively grasp the mechanisms underlying the dormancy period of Mtb.…”

Section: Introductionmentioning

confidence: 99%

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Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products

Shah,

Khan,

Ahmad

et al. 2023

Front. Pharmacol.

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Tuberculosis (TB), an infectious disease caused by multi-drug resistant Mycobacterium tuberculosis (Mtb), has been a global health concern. Mtb affects over a third of the world’s population, causing two million deaths annually due to its dormancy and propensity to spread infection during this period. Resuscitation-promoting factor B (RpfB) plays a pivotal role in the growth of Mtb during dormant periods, making it a critical target for eliminating Mtb and curing TB. Gymnema sylvestre is a famous medicinal plant with several medicinal properties, including antimicrobial activity; however, the therapeutic potential of the various reported metabolites of this plant against Mtb has not yet been explored. The aim of this study was to explore the reported natural products of G. sylvestre against the RpfB of the Mtb. A total of 131 reported secondary metabolites of this plant were collected and virtually screened against the RpfB. We particularly targeted the Glu292 residue of RpfB as it is crucial for the catalysis of this protein. From our in-house library, 114 compounds showed a binding affinity higher than the standard drug. The binding stability of the top three lead compounds was further confirmed through MD simulation analysis. Drug likeness analyses indicated that the ten hits had zero violations of the Lipinski rule of five. In addition, analyses of pharmacokinetics, toxicity, and target prediction revealed that the top compounds are devoid of toxicity and do not affect human proteins. Additionally, they reflect multifaceted approach as anti-TB agents. Our selected hits not only exhibit molecular properties favoring physiological compatibility but also exhibit properties enhancing their potential efficacy as therapeutic candidates. The compounds investigated here are worthy of experimental validation for the discovery of novel treatments against TB. Further, this study also provides a promising avenue for research on the pharmacological potential of G. sylvestre.

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“…All compounds selected for electrophysiology studies were re-docked using AutoDock Vina in USCF Chimera ( Trott and Olson, 2010 ; Labbé et al, 2015 ; Celie et al, 2004 ; Yu et al, 2021 ; Eberhardt et al, 2021 ) to validate hit compounds and to compare the binding of hit compounds to CHAPS and classical neurotransmitters. This process follows the methods outlined by Rabaan and colleagues ( Rabaan et al, 2023 ). The CHAPS Alpo4 structure and all 12 compounds were prepared for docking using the in-built Dock Prep tool with default setting ( Shapovalov and Dunbrack, 2011 ; Wang et al, 2006 ), which adds in polar hydrogens and charges.…”

Section: Methodsmentioning

confidence: 99%

Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor

Gieter

Gallagher

Wijckmans

et al. 2023

eLife

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Cys-loop receptors or pentameric ligand-gated ion channels are mediators of electrochemical signaling throughout the animal kingdom. Because of their critical function in neurotransmission and high potential as drug targets, Cys-loop receptors from humans and closely related organisms have been thoroughly investigated, whereas molecular mechanisms of neurotransmission in invertebrates are less understood. When compared with vertebrates, the invertebrate genomes underwent a drastic expansion in the number of the nACh-like genes associated with receptors of unknown function. Understanding this diversity contributes to better insight into the evolution and possible functional divergence of these receptors. In this work, we studied orphan receptor Alpo4 from an extreme thermophile worm Alvinella pompejana. Sequence analysis points towards its remote relation to characterized nACh receptors. We solved the cryo-EM structure of the lophotrochozoan nACh-like receptor in which a CHAPS molecule is tightly bound to the orthosteric site. We show that the binding of CHAPS leads to extending of the loop C at the orthosteric site and a quaternary twist between extracellular and transmembrane domains. Both the ligand binding site and the channel pore reveal unique features. These include a conserved Trp residue in loop B of the ligand binding site which is flipped into an apparent self-liganded state in the apo structure. The ion pore of Alpo4 is tightly constricted by a ring of methionines near the extracellular entryway of the channel pore. Our data provide a structural basis for a functional understanding of Alpo4 and hints towards new strategies for designing specific channel modulators.

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Anti-tubercular activity evaluation of natural compounds by targeting Mycobacterium tuberculosis resuscitation promoting factor B inhibition: An in silico study

Cited by 7 publications

References 40 publications

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection

Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products

Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor

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