Computational design of medicinal compounds to inhibit RBD-hACE2 interaction in the Omicron variant: unveiling a vulnerable target site

Shahab, Muhammad; Akter, Shahina; Sarkar, Md. Murshed Hasan; Banu, Tanjina Akhtar; Goswami, Barna; Chowdhury, Sanjana Fatema; Naser, Safaei; Habib, Md. Ahashan; Shaikh, Arif V.; Saki, Morteza; Zheng, Guojun; Khan, Mala

doi:10.1016/j.imu.2023.101281

Cited by 9 publications

(6 citation statements)

References 38 publications

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“…The use of the MMPBSA.py script in the MD simulation run, trajectories were identified, which were further used in calculating the binding free energy ( Shahab et al, 2023b ). For calculating the binding free energy of any complexes, including protein-ligand, nucleic acid-protein, and protein-protein, this type of approach was used ( Khan et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches

Shahab,

Zheng,

Alshabrmi

et al. 2023

Front. Mol. Biosci.

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Aldose reductase (AR) is an important target in the development of therapeutics against hyper-glycemia-induced health complications such as retinopathy, etc. In this study, we employed a combination of structure-based drug design, molecular simulation, and free energy calculation approaches to identify potential hit molecules against anti-diabetic (anti-hyperglycemic)-induced health complications. The 3D structure of aldoreductase was screened for multiple compound libraries (1,00,000 compounds) and identified as ZINC35671852, ZINC78774792 from the ZINC database, Diamino-di nitro-methyl dioctyl phthalate, and Penta-o-galloyl-glucose from the South African natural compounds database, and Bisindolylmethane thiosemi-carbazides and Bisindolylme-thane-hydrazone from the Inhouse database for this study. The mode of binding interactions of the selected compounds later predicted their aldose reductase inhibitory potential. These com-pounds interact with the key active site residues through hydrogen bonds, salt bridges, and π-π interactions. The structural dynamics and binding free energy results further revealed that these compounds possess stable dynamics with excellent binding free energy scores. The structures of the lead inhibitors can serve as templates for developing novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is warranted. The current study is the first to design small molecule inhibitors for the aldoreductase protein that can be used in the development of therapeutic agents to treat diabetes.

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Section: Methodsmentioning

confidence: 99%

Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches

Shahab,

Zheng,

Alshabrmi

et al. 2023

Front. Mol. Biosci.

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“…The MD simulations were conducted using the Amber 20 software package (University of California, San Francisco, CA, USA), and the force field parameters for the molecules were generated utilizing the Antechamber module with the general AMBER force field [ 29 ]. The system, consisting of DH, IBU, and organic solvents, was placed within a periodic boundary box and solvated with TIP3P water.…”

Section: Methodsmentioning

confidence: 99%

“…Density profiles of DH and IBU molecules were probed using VMD’s density profile tool to observe the density distribution of molecules in the simulation box coordinates [ 30 ]. The root-mean-squared deviation (RMSD) of the matrix, IBU, and DH was obtained using the cpptraj module [ 29 ]. Diffusion constants, reflecting the migration distance from the initial position, were calculated using the ptraj module with the time-evolved trajectory of the simulation.…”

Section: Methodsmentioning

confidence: 99%

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Computational Insight of Phase Transformation and Drug Release Behaviour of Doxycycline-Loaded Ibuprofen-Based In-Situ Forming Gel

Puyathorn,

Tamdee,

Sirirak

et al. 2023

Pharmaceutics

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This research investigates the gel formation behaviour and drug-controlling performance of doxycycline-loaded ibuprofen-based in-situ forming gels (DH-loaded IBU-based ISGs) for potential applications in periodontal treatment. The investigation begins by exploring the physical properties and gel formation behaviour of the ISGs, with a particular focus on determining their sustained release capabilities. To gain a deeper understanding of the molecular interactions and dynamics within the ISGs, molecular dynamic (MD) simulations are employed. The effects of adding IBU and DH on reducing surface tension and water tolerance properties, thus affecting molecular properties. The phase transformation phenomenon is observed around the interface, where droplets of ISGs move out to the water phase, leading to the precipitation of IBU around the interface. The optimization of drug release profiles ensures sustained local drug release over seven days, with a burst release observed on the first day. Interestingly, different organic solvents show varying abilities to control DH release, with dimethyl sulfoxide (DMSO) demonstrating superior control compared to N-Methyl-2-pyrrolidone (NMP). MD simulations using AMBER20 software provide valuable insights into the movement of individual molecules, as evidenced by root-mean-square deviation (RMSD) values. The addition of IBU to the system results in the retardation of IBU molecule movement, particularly evident in the DMSO series, with the diffusion constant value of DH reducing from 1.2452 to 0.3372 and in the NMP series from 0.3703 to 0.2245 after adding IBU. The RMSD values indicate a reduction in molecule fluctuation of DH, especially in the DMSO system, where it decreases from over 140 to 40 Å. Moreover, their radius of gyration is influenced by IBU, with the DMSO system showing lower values, suggesting an increase in molecular compactness. Notably, the DH-IBU configuration exhibits stable pairing through H-bonding, with a higher amount of H-bonding observed in the DMSO system, which is correlated with the drug retardation efficacy. These significant findings pave the way for the development of phase transformation mechanistic studies and offer new avenues for future design and optimization formulation in the ISG drug delivery systems field.

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“…Molecular docking is the technique used to assess protein-ligand interactions. The Insilico drug design approach is gaining traction as a valuable tool to identify new potential drugs for a range of diseases [15,30,31].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Mechanism and discovery of potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis

Ullah,

Shahab,

Yaseen

et al. 2023

Preprint

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The rise of antibiotic-resistant Mycobacterium tuberculosis (MTB) has led to a reduction in the availability of effective medications for tuberculosis therapy, resulting in increased morbidity and mortality globally. Tuberculosis primarily affects the lungs but can also spread to the brain and spine. Pyrazinamide (PZA) is considered to be the most potent drug but it also shows resistance due to mutation at the position G97D. However, the Mechanism of PZA drug resistance towards Mtb PZase is unclear. Moreover, due to mutations that provide PZA resistance, there is no such evidence about the structural dynamics of Mtb PZase protein. Here we aimed to perform molecular docking, pharmacophore modeling, virtual Screening, and MD simulation, to explore the Mtb PZase protein resistance mechanism toward the PZA drug due to mutation at the G97D position as well as compare the Wild-type and Mutant-type PZA bound systems. From the analysis, the Wild-type shows good interaction as compared to Mutant-type PZA bound systems. Then we performed pharmacophore-based virtual screening against commercially available databases i.e. ZINC and Chembridge. Finally, we selected a total of 5 lead compounds based on docking score and good interaction. The selected compounds considered has a good ADMET property, because the compound shows no pan Assay interference (PAINS) indicating that these compound could be useful inhibitors of Mutant-type PZA bound systems.

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Computational design of medicinal compounds to inhibit RBD-hACE2 interaction in the Omicron variant: unveiling a vulnerable target site

Cited by 9 publications

References 38 publications

Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches

Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches

Computational Insight of Phase Transformation and Drug Release Behaviour of Doxycycline-Loaded Ibuprofen-Based In-Situ Forming Gel

Exploring the Mechanism and discovery of potential hits to improve the treatment of pyrazinamide-resistant Mycobacterium tuberculosis

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