Molecular Modeling: A Search for a Calpain Inhibitor as a New Treatment for Cataractogenesis

Stuart, Blair G.; Coxon, James M.; Morton, James D.; Abell, Andrew D.; McDonald, D. Quentin; Aitken, Steven G.; Jones, Matthew A.; Bickerstaffe, R.

doi:10.1021/jm200471r

Cited by 20 publications

(14 citation statements)

References 71 publications

(96 reference statements)

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“…[149] Binding site optimization has been shown to be particularly beneficial for GPCR homology models. [45,47,150,151] Homology models were used for docking into neuronal nicotinic receptor, [152] Trypanosoma brucei phosphodiesterases, [153] prostaglandin E synthase 1, [154] aryl hydrocarbon receptor transcription factor, [155] as well as VS against the following: the s1 receptor, [156] calpain, [157] kinases, [158][159][160][161] and GPCRs. [45,47,126,151,[162][163][164][165] Structural validation studies For us to have an expectation that a given docking setup (i.e., choice of program, scoring function, and approaches to deal with ligand and receptor flexibility) will deliver reliable results, it must be validated for a system under investigation (i.e., ligand and receptor type).…”

Section: Docking Into Homology Modelsmentioning

confidence: 99%

Latest developments in molecular docking: 2010–2011 in review

Yuriev

Ramsland

2013

J of Molecular Recognition

291

205

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The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. The main developments in docking in this period, covered in this review, are receptor flexibility, solvation, fragment docking, postprocessing, docking into homology models, and docking comparisons. Several new, or at least newly invigorated, advances occurred in areas such as nonlinear scoring functions, using machine-learning approaches. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design. Where appropriate, we refer readers to exemplar case studies.

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Section: Docking Into Homology Modelsmentioning

confidence: 99%

Latest developments in molecular docking: 2010–2011 in review

Yuriev

Ramsland

2013

J of Molecular Recognition

291

205

View full text Add to dashboard Cite

show abstract

“…Connolly's methods attempt to align points on surfaces by minimizing the angle between the surfaces of opposing molecules. Therefore, a rigid body approximation is still the standard for many protein-protein docking techniques [37][38][39][40][41]. The use of potential energy grids was established by Good ford, and various docking programs use such grid representations for energy calculations [42].…”

Section: Molecular Illustration Of Docking and Involve Methodologymentioning

confidence: 99%

Molecular Docking an Enchanted Way in The Discovery of Novel Molecule in Designing Drug: A Focused Review

Mohan¹,

Singh²,

Maurya³

et al. 2018

RPHS

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Current review paper revolves around the method of molecular docking. It involves regarding the basics of the docking studies. It also focused on the biological and pharmaceutical significance of the molecular docking, considerable efforts have been directed towards improving the methods used to predict docking. There is general concept about molecular docking is lock and key in which the finding is correct relative orientation of the key which can best fitted into the lock and then the lock can be open easily. How the accurate structure can be designed and what are the correct activities are predicted are the main two aims of the docking studies are preferred in the given studies and some examples are also added within the review for the evidence which supports the importance of docking studies.

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“…Prior to protein preparation, the Ser115 residue of 1KXR was mutated to Cys115, so as to mimic the protein in physiological conditions; this was done using the standard mutation protocol of the Schrodinger software. 16,24 Chemical accuracy was ensured by addition of hydrogen atoms, correcting the bond orders and by neutralizing the side-chains which were neither close to the binding cavity nor were involved in the construction of salt bridges. The structure prepared underwent minimization by adopting the Protein Preparation Wizard with optimal potential to create the liquid simulation (OPLS)-2005 force field (FF) at an intermediate docking stage.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Structure-Based Virtual Screening and Biological Evaluation of a Calpain Inhibitor for Prevention of Selenite-Induced Cataractogenesis in an in Vitro System

Muralidharan

Selvaraj

Sheu

et al. 2015

J. Chem. Inf. Model.

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Calpains belong to the family of calcium-dependent, structurally related intracellular cysteine proteases that exhibit significant functions in evolution of different types of cataracts in human as well as animal models. Application of calpain inhibitors generated through a virtual screening workflow may provide new avenues for the prevention of cataractogenesis. Hence, in the current study, compounds were first screened for potent calpain inhibitory activity by employing a structure-based approach, and the screening results were then validated through biological experiments in rat lenses. A hit compound, HTS08688, was obtained by structure-based virtual screening. A micromolar concentration of HTS08688 was found to prevent in vitro cataractogenesis in isolated Wistar rat lenses, while maintaining the antioxidant and calcium concentrations at near normal levels. Inhibition of superoxide anion generation, as observed through cytochemical localization studies, and maintenance of structural integrity, as demonstrated by histological analysis of lenticular tissue, also suggested that HTS08688 can ameliorate the cataractous condition induced by selenite in an in vitro rodent model. A cell proliferation assay was performed; the IC 50 value of the screened calpain inhibitor, HTS08688, against human lenticular epithelial cells-b3 was found to be 177 μM/mL. This combined theoretical and experimental approach has demonstrated a potent lead compound, HTS08688, that exhibits putative anticataractogenic activity by virtue of its potential to inhibit calpain.

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Molecular Modeling: A Search for a Calpain Inhibitor as a New Treatment for Cataractogenesis

Cited by 20 publications

References 71 publications

Latest developments in molecular docking: 2010–2011 in review

Latest developments in molecular docking: 2010–2011 in review

Molecular Docking an Enchanted Way in The Discovery of Novel Molecule in Designing Drug: A Focused Review

Structure-Based Virtual Screening and Biological Evaluation of a Calpain Inhibitor for Prevention of Selenite-Induced Cataractogenesis in an in Vitro System

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