Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study

Badr, Esraa A A; Abdelrahman, Alaa H. M.; Almansour, Nahlah Makki; Shawky, Ahmed M.; Mekhemer, Gamal A. H.; Moustafa, Mahmoud; Atia, Mohamed A. M.

doi:10.1007/s12013-021-00985-y

Cited by 17 publications

(8 citation statements)

References 44 publications

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“…The general AMBER force field (GAFF2) was employed to parameterize NPASS compounds [ 33 ], while the ABCB1 transporter was parameterized using an AMBER force field of 14SB [ 34 ]. The minutiae of employed MD simulations are characterized in [ 35 , 36 , 37 ]. In this work, both implicit- and explicit-solvent MD simulations were executed.…”

Section: Computational Methodologymentioning

confidence: 99%

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

et al. 2022

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The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.

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Section: Computational Methodologymentioning

confidence: 99%

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

et al. 2022

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“…Pibrentasvir is one of the prospective drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors. Pibrentasvir was proposed as a therapeutic option for multidrug-resistant cancers via targeting ABCG2 transporter based on an in silico drug discovery study [ 19 ]. Therefore, the binding affinity of pibrentasvir with ABCG2 transporter was estimated over 100 ns MD simulations and compared to NPACT00968 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While virtual screening of clinical and investigational drugs as ABCG2 inhibitors revealed that pibrentasvir, venetoclax, and ledipasvir would be promising inhibitors (calc. k i = 1.14 nM, 16.4 nM, and 8.19 pM, respectively) toward ABCG2 transporter [ 19 ]. Chemical databases were filtrated toward the ABCG2 transporter to discover prospective ABCG2 inhibitors utilizing advanced computational approaches, revealing eight potential inhibitors with binding affinities less than − 55.8 kcal/mol [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study

et al. 2022

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ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. − 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (− 100.4, − 94.7, and − 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed. Graphical abstract

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“…39 The minutiae of the utilized MD simulations are explicated in ref. 40–44. In succinct, the investigated inhibitors were characterized with the aid of the General AMBER Force Field (GAFF2).…”

Section: Methodsmentioning

confidence: 99%

Versisterol, a new endophytic steroid with 3CL protease inhibitory activity from Avicennia marina (Forssk.) Vierh.

Elsbaey

Hegazy

2022

RSC Adv.

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Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study

Cited by 17 publications

References 44 publications

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study

Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study

Versisterol, a new endophytic steroid with 3CL protease inhibitory activity from Avicennia marina (Forssk.) Vierh.

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