Computational investigation of binding mechanism of substituted pyrazinones targeting corticotropin releasing factor-1 receptor deliberated for anti-depressant drug design

Article

Author: Kalra, Sourav ; Pratap Singh, Hemendra ; Kumar, Neeraj ; Venkatachalam, T. ; Shekhar, Mishra Shashank ; Sharma, Chandra Shekhar

In spite of various research investigations towards anti-depressant drug discovery program, no one drug has not yet launched last 20 years. Corticotropin-releasing factor-1 (CRF-1) is one of the most validated targets for the development of antagonists against depression, anxiety and post-traumatic stress disorders. Various research studies suggest that pyrazinone based CRF-1 receptor antagonists were found to be highly potent and efficacious. In this research investigation, we identified the pharmacophore and binding pattern through 2D and 3D-QSAR and molecular docking respectively. Molecular dynamics studies were also performed to explore the binding pattern recognition. We establish the relationship between activity and pharmacophoric features to design new potent compounds. The best 2D-QSAR model was generated through multiple linear regression method with r² value of 0.97 and q² value of 0.89. Also 3D-QSAR model was obtained through k-nearest neighbor molecular field analysis method with q² value of 0.52 and q²_se value of 0.36. Molecular docking and binding energy were also evaluated to define binding patterns and pharmacophoric groups, including (i) hydrogen bond with residue Asp284, Glu305 and (ii) π-π stacking with residue Trp9. Compound 11i has the highest binding affinity compared to reference compounds, so this compound could be a potent drug for stress related disorders. Most of the compounds, including reference compounds were found within acceptable range of physicochemical parameters. These observations could be provided the leads for the design and optimization of novel CRF-1 receptor antagonists. Communicated by Ramaswamy H. Sarma.

28 Sep 2015·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

Decoding the Role of Water Dynamics in Ligand–Protein Unbinding: CRF₁R as a Test Case

Q2 · CHEMISTRY

Article

Author: Weiss, Dahlia R. ; Deflorian, Francesca ; Bortolato, Andrea ; Mason, Jonathan S.

The residence time of a ligand-protein complex is a crucial aspect in determining biological effect in vivo. Despite its importance, the prediction of ligand koff still remains challenging for modern computational chemistry. We have developed aMetaD, a fast and generally applicable computational protocol to predict ligand-protein unbinding events using a molecular dynamics (MD) method based on adiabatic-bias MD and metadynamics. This physics-based, fully flexible, and pose-dependent ligand scoring function evaluates the maximum energy (RTscore) required to move the ligand from the bound-state energy basin to the next. Unbinding trajectories are automatically analyzed and translated into atomic solvation factor (SF) values representing the water dynamics during the unbinding event. This novel computational protocol was initially tested on two M3 muscarinic receptor and two adenosine A2A receptor antagonists and then evaluated on a test set of 12 CRF1R ligands. The resulting RTscores were used successfully to classify ligands with different residence times. Additionally, the SF analysis was used to detect key differences in the degree of accessibility to water molecules during the predicted ligand unbinding events. The protocol provides actionable working hypotheses that are applicable in a drug discovery program for the rational optimization of ligand binding kinetics.

13 Jun 2013·Journal of Medicinal Chemistry

Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand

Article

Author: Chappie, Thomas A. ; Skaddan, Marc B. ; Wager, Travis T. ; Hou, Xinjun ; Humphrey, John M. ; Helal, Christopher J. ; Grimwood, Sarah ; Chen, Laigao ; McCarthy, Timothy J. ; Bocan, Thomas ; Zasadny, Kenneth ; Verhoest, Patrick R. ; Beck, Elizabeth M. ; Lu, Jiemin ; Villalobos, Anabella ; Zhang, Lei ; Heck, Steven D.

To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as negative controls. A systematic analysis of these ligands identified a set of preferred parameters for physicochemical properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-[(18)F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [(18)F]PF-05270430 (5).

100 Deals associated with SK-696

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Preclinical	United States	DuPont Pharmaceuticals Co.	26 Jan 2000
Depressive Disorder	Preclinical	United States	Bristol Myers Squibb Co.	-

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