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

Abstract

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

GRAPHICAL ABSTRACT

ABBREVIATIONS
CRF	=	corticotropin-releasing factor
HPA	=	hypothalamus-pituitary-adrenocortical axis
kNN MFA	=	k-nearest neighbor molecular field analysis
MD	=	molecular dynamics
MLR	=	multiple linear regression
MM/GBSA	=	molecular mechanics/generalized Born surface area
OLS	=	ordinary least squares regression
OPLS	=	optimized potential for liquid simulations
POPC	=	1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
QSAR	=	quantitative structure-activity relationship
RMSD	=	root mean square deviation
RMSF	=	root mean square fluctuation
SA	=	simulated annealing
XP	=	extra precision

Keywords:

• CRF-1
• molecular docking
• Prime MM/GBSA
• molecular dynamics
• QSAR

Acknowledgments

The authors are thankful to Centre for Human Genetics & Molecular Medicine, Central University of Punjab for providing computational facilities to accomplish this research work.

Disclosure statement

No potential conflict of interest was reported by the authors.