Virtual screening against Mycobacterium tuberculosis dihydrofolate reductase: Suggested workflow for compound prioritization using structure interaction fingerprints

Kumar, Ashutosh; Siddiqi, Mohammad Imran

doi:10.1016/j.jmgm.2008.08.005

Cited by 18 publications

(15 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Talele et al have highlighted successful drugs such as Captopril (Capoten ® , Bristol Myers-Squibb, New York, NY, USA), Saquinavir (Invirase ® , Hoffmann-La Roche, Basel, Switzerland) and Zanamivir (Relenza ® , Gilead Sciences, Foster City, CA, USA) that have been developed using this strategy [ 21 ]. SBDD methods have also been employed to study the inhibitors of Mycobacterium tuberculosis [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

et al. 2018

View full text Add to dashboard Cite

Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans. The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers. In addition, emerging drug resistance to treatment poses great challenges. There is a need to identify novel natural product-derived lead compounds, which are potent and efficacious for the treatment of Buruli ulcer. Natural products present a rich diversity of chemical compounds with proven activity against various infectious diseases, and therefore, are considered in this study. This study sought to computationally predict natural product-derived lead compounds with the potential to be developed further into potent drugs with better therapeutic efficacy than the existing anti-buruli ulcer compounds. The three-dimensional (3D) structure of Isocitrate lyase (ICL) of Mycobacterium ulcerans was generated using homology modeling and was further scrutinized with molecular dynamics simulations. A library consisting of 885 compounds retrieved from the AfroDb database was virtually screened against the validated ICL model using AutoDock Vina. AfroDb is a compendium of “drug-like” and structurally diverse 3D structures of natural products originating from different geographical regions in Africa. The molecular docking with the ICL model was validated by computing a Receiver Operating Characteristic (ROC) curve with a reasonably good Area Under the Curve (AUC) value of 0.89375. Twenty hit compounds, which docked firmly within the active site pocket of the ICL receptor, were assessed via in silico bioactivity and pharmacological profiling. The three compounds, which emerged as potential novel leads, comprise ZINC38143792 (Euscaphic acid), ZINC95485880, and ZINC95486305 with reasonable binding energies (high affinity) of −8.6, −8.6, and −8.8 kcal/mol, respectively. Euscaphic acid has been reported to show minimal inhibition against a drug-sensitive strain of M. tuberculosis. The other two leads were both predicted to possess dermatological activity while one was antibacterial. The leads have shown promising results pertaining to efficacy, toxicity, pharmacokinetic, and safety. These leads can be experimentally characterized to assess their anti-mycobacterial activity and their scaffolds may serve as rich skeletons for developing anti-buruli ulcer drugs.

show abstract

Section: Introductionmentioning

confidence: 99%

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This method is used for rapid clustering and analysis of large number of complexes and identification of compact interaction patterns [28]. Fingerprints were generated using residue numbers that are in contact with the protein and the inhibitors.…”

Section: Structural Interaction Fingerprints (Sift) Methodology and Imentioning

confidence: 99%

Targeting the Epidermal Growth Factor Receptor: Exploring the Potential of Novel Inhibitor N-(3-Ethynylphenyl)-6, 7-bis (2-methoxyethoxy) Quinolin- 4-Amine Using Docking and Molecular Dynamics Simulation

Gupta

Misra²,

Pant³

et al. 2012

PPL

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer related death. The epidermal growth factor receptor (EGFR) pathway is over expressed in HNSCC. EGFR regulates the HNSCC by inducing signalling events responsible for regulating key tumorigenic processes such as proliferation, inhibition of apoptosis, cell adhesion/ motility, growth and survival. Present study evaluates the potential of N-(3-Ethynylphenyl)-6, 7-bis (2-methoxyethoxy) quinolin-4-amine as a new inhibitor for EGFR. We have explored the binding and inhibitory potential of the compound using molecular docking, structural interactions fingerprinting and molecular dynamics studies. The inhibitor exhibits extensive interactions with the EGFR catalytic site in the form of hydrogen bonds, pi-pi bond and salt bridges. It shows high specificity and binding affinity towards the protein. The compound can further be explored for its potential to serve in the diagnosis and treatment of HNSCC. The quantitative prediction provides a scope for future experimental testing, facilitating the understanding of the crosstalks between signalling pathways.

show abstract

“…Structural interaction fingerprints (SIFts) were used for one-dimensional binary representation of contact between ligands and macromolecule amino acids. The advantage of using the SIFt method is in generating protein-ligand interaction fingerprints to elucidate the interaction patterns [49][50][51]. Predefined binding site amino acid residues involved in ligand binding were used for SIFt calculations for both sets of ligands (inhibitors of cathepsin B and virtual screen hits), while hydrogen bond interactions between ligands and amino acids were identified by UCSF Chimera software with default settings.…”

Section: Construction Of Structural Interaction Fingerprints (Sifts) Similarity Analysis and Hierarchical Clusteringmentioning

confidence: 99%

Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Chitranshi

Kumar

Sheriff

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

show abstract

Virtual screening against Mycobacterium tuberculosis dihydrofolate reductase: Suggested workflow for compound prioritization using structure interaction fingerprints

Cited by 18 publications

References 32 publications

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

Targeting the Epidermal Growth Factor Receptor: Exploring the Potential of Novel Inhibitor N-(3-Ethynylphenyl)-6, 7-bis (2-methoxyethoxy) Quinolin- 4-Amine Using Docking and Molecular Dynamics Simulation

Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Contact Info

Product

Resources

About