Pharmacophore modelling-based virtual screening of compound is a ligand-based approach and is useful when the 3D structure of target is not available but a few known active compounds are known. Pharmacophore mapping studies were undertaken for a set of 50？N3-phenylpyrazinones possessing Corticotropin-releasing Factor 1 (CRF 1) antagonistic activity. Six point pharmacophores with two hydrogen bond acceptors, one hydrogen bond donor, two hydrophobic regions, and one aromatic ring as pharmacophoric features were developed. Amongst them the pharmacophore hypothesis AADHHR.47 yielded a statistically significant 3D-QSAR model with 0.803 as value and was considered to be the best pharmacophore hypothesis. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.91 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore were expected to be useful for the design of selective CRF 1 receptor antagonists. 1. Introduction Anxiety and depression are among the most common disorders seen in medical practice. The coexistence of anxiety and depression with medical illness is a topic of considerable clinical and research interest [1]. Depression is a serious mental health problem, with significant consequences in terms of human suffering, lost productivity, and even loss of life [2]. Corticotropin-releasing factor 1 (CRF 1) receptor antagonists have been sought since the stress-secreted peptide (adrenocorticotropin-releasing hypothalamic peptide) was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF 1 receptor antagonist as antidepressants, CRF 1 receptor antagonist might be novel pharmacotherapies for anxiety and addiction [3]. Two well-characterized receptor subtypes, CRF 1 and CRF 2, have been identified. These G-protein-coupled receptors are widely distributed throughout the central and peripheral nervous systems [4]. Clinical evidence supports the hypothesis that overproduction of CRF 1？？may underlie the pathology of depression, anxiety, and stress-related disorders and suggests that CRF 1 receptor antagonists could be useful for the treatment of these conditions [5]. To reduce the overall cost associated with the discovery and development of a new drug, the computer-aided molecular design methods have been identified as the most promising candidates to focus on the experimental efforts in modern medicinal chemistry. Pharmacophore mapping is one of the major elements
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