Chemogenomics in drug discovery: computational methods based on the comparison of binding sites

2012 ◽  
Vol 4 (15) ◽  
pp. 1971-1979 ◽  
Author(s):  
Anna Vulpetti ◽  
Tuomo Kalliokoski ◽  
Francesca Milletti
Keyword(s):  
Drug Discovery ◽  
Computational Methods ◽  
Binding Sites

Structural dynamics and allostery of Rab proteins: strategies for drug discovery and design

2020 ◽  
Author(s):  
Ammu Prasanna Kumar ◽  
Chandra S Verma ◽  
Suryani Lukman
Keyword(s):  
Drug Discovery ◽  
Computational Methods ◽  
Structural Dynamics ◽  
Binding Sites ◽  
Structural Data ◽  
Extraction Methods ◽  
Rab Proteins ◽  
Nucleotide Binding Sites ◽  
Using Data ◽  
Guanosine Triphosphatase

Abstract Rab proteins represent the largest family of the Rab superfamily guanosine triphosphatase (GTPase). Aberrant human Rab proteins are associated with multiple diseases, including cancers and neurological disorders. Rab subfamily members display subtle conformational variations that render specificity in their physiological functions and can be targeted for subfamily-specific drug design. However, drug discovery efforts have not focused much on targeting Rab allosteric non-nucleotide binding sites which are subjected to less evolutionary pressures to be conserved, hence are likely to offer subfamily specificity and may be less prone to undesirable off-target interactions and side effects. To discover druggable allosteric binding sites, Rab structural dynamics need to be first incorporated using multiple experimentally and computationally obtained structures. The high-dimensional structural data may necessitate feature extraction methods to identify manageable representative structures for subsequent analyses. We have detailed state-of-the-art computational methods to (i) identify binding sites using data on sequence, shape, energy, etc., (ii) determine the allosteric nature of these binding sites based on structural ensembles, residue networks and correlated motions and (iii) identify small molecule binders through structure- and ligand-based virtual screening. To benefit future studies for targeting Rab allosteric sites, we herein detail a refined workflow comprising multiple available computational methods, which have been successfully used alone or in combinations. This workflow is also applicable for drug discovery efforts targeting other medically important proteins. Depending on the structural dynamics of proteins of interest, researchers can select suitable strategies for allosteric drug discovery and design, from the resources of computational methods and tools enlisted in the workflow.

Fragment Dissolved Molecular Dynamics: A systematic and efficient method to locate binding sites

2020 ◽  
Author(s):  
Cristian Privat ◽  
Jose M. Granadino-Roldan ◽  
Jordi Bonet ◽  
Maria Santos Tomas ◽  
Juan Jesús Pérez ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Computational Methods ◽  
Efficient Method ◽  
Binding Sites ◽  
Protein Denaturation ◽  
Fragment Based Drug Discovery

Diverse computational methods to support Fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy to support FBDD campaigns, they exhibit some drawbacks such as protein denaturation...

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

scholarly journals The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

2019 ◽  
Vol 20 (24) ◽  
pp. 6218 ◽  
Author(s):  
Joseph T. Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Binding Sites ◽  
Binding Pocket ◽  
Biologically Active ◽  
Surface Receptors ◽  
Beneficial Effects ◽  
Light Sensing ◽  
Potential Binding ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.

scholarly journals Structural elucidation of ligand binding sites in family B GPCRs and their application in drug discovery 

2016 ◽  
Vol 72 (a1) ◽  
pp. s24-s24
Author(s):  
Ali Jazayeri ◽  
Andrew Doré ◽  
Daniel Lamb ◽  
Harini Krishnamurthy ◽  
Stacey Southall ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Ligand Binding ◽  
Binding Sites ◽  
Structural Elucidation ◽  
Ligand Binding Sites

Pocketome of Human Kinases: Prioritizing the ATP Binding Sites of (Yet) Untapped Protein Kinases for Drug Discovery

2015 ◽  
Vol 55 (3) ◽  
pp. 538-549 ◽  
Author(s):  
Andrea Volkamer ◽  
Sameh Eid ◽  
Samo Turk ◽  
Sabrina Jaeger ◽  
Friedrich Rippmann ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Kinases ◽  
Binding Sites ◽  
Atp Binding
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