In connection to developing non-steroidal estrogen analogs, the present study explores the pharmacophore of triphenylacrylonitriles (Fig. 1) for binding affinity to estrogen receptor using Electrotopological State (E-State) indices of constituting atoms. The analysis shows the efficacy of E-State index in developing statistically acceptable model, which defines the electronic environment and topological states of diverse atoms in a molecule. The investigation concluded that electrophilic substitutions at C 6 and C 18 of the phenyl rings (A and C rings respectively) attached to C 2 and C 1 of ethylenic moiety, along with presence of hydroxyl substitution at C 12 (ring B) and no. of non-hydrogen free terminal atoms of the molecule have influence on the binding affinity to the estrogen receptor. © 2005 Pharmaceutical Society of Japan.

ACHINTYA SAHA

Chemical Technology

S MUKHERJEE

A MUKHERJEE

Fulltext

University of Calcutta (informally known as Calcutta University or CU) is a collegiate public state university located in Kolkata, West Bengal, India.&nbsp;Within India it is recognized as a &quot;Five-Star University&quot; and accredited &quot;A&quot; Grade by National Assessment and Accreditation Council.

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The University of Calcutta has secured the Fifth position among the Universities of India in the prestigious &quot;Indian University Ranking 2019&quot; list, released by the NIRF of the Ministry of Human Resource Development, Government of India.

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It was established on 24 January 1857, and was one of the first institutions in Asia to be established as a multidisciplinary and Western-style university. Its alumni and faculty include several heads of state, heads of government, social reformers, prominent artists, only academy award winner and Dirac medal winner in India, many Fellows of the Royal Society and five Nobel laureates as of 2019 which is highest in South Asia.

University Of Calcutta

Biological and Pharmaceutical Bulletin

Estrogens, a group of steroid hormones, act primarily by regulating gene expression after binding with estrogen receptor (ER), a nuclear ligand-activated transcription factor, translocates to the nucleus after dimer formation, enhances the gene transcription. Estrogen Receptor Modulators (ERMs) have selective agonist and antagonist effects to different tissues, and the purpose of research on ERMs is to identify new potent and less toxic drug molecules. The present study has been focused on finding the structural requirements of ER ligand, using receptor-independent pharmacophore space modeling studies that can explore 3D structural features and configurations, responsible for the biological activity of structurally diverse compounds. The studies show (R=0.945, RMSD=2.186, Δcost=677.354) the importance of hydrogen bond acceptors in the aromatic rings and a planner hydrophobic region in the molecular architecture along with critical geometrical distance between features are effectively crucial for binding with ER. © 2008 Pharmaceutical Society of Japan.

Molecular design based on receptor-independent pharmacophore: Application to estrogen receptor ligands

Estrogens, a group of steroid hormones, act primarily by regulating gene expression after binding with estrogen receptor (ER), a nuclear ligand-activated transcription factor, translocates to the nucleus after dimer formation, enhances the gene transcription. Estrogen Receptor Modulators (ERMs) have selective agonist and antagonist effects to different tissues, and the purpose of research on ERMs is to identify new potent and less toxic drug molecules. The present study has been focused on finding the structural requirements of ER ligand, using receptor-independent pharmacophore space modeling studies that can explore 3D structural features and configurations, responsible for the biological activity of structurally diverse compounds. The studies show (R=0.945, RMSD=2.186, Ocost=677.354) the importance of hydrogen bond acceptors in the aromatic rings and a planner hydrophobic region in the molecular architecture along with critical geometrical distance between features are effectively crucial for binding with ER.

Research on Selective Estrogen Receptor Modulators (SERMs) has been driven by interest in discovering target selective molecules. In view of such significance, the present work explored the pharmacophores of estrogen receptor (ER) subtypes specific binding affinities of diverse compounds belonging to the category of bridged bicyclic-1,1-diarylethylene derivatives. Implementing classical QSAR and CATALYST based space-modeling approaches, it has been explored that attachment of aryl ring systems to unsaturated linkages, availability of phenolic hydroxyl group, global hydrophobicity, and stereochemistry of certain functional groups might be important for governing the subtype specific estrogenic behavior of this group of compounds. Supplementing this deduction, critical interfeature distances between hydrogen bond acceptor, hydrophobic, and ring aromatic features along with steric influence are found to primarily influence the ER-subtypes specific binding of this series of compounds. © 2007 American Chemical Society.

Journal of Chemical Information and Modeling

Pharmacophore mapping of selective binding affinity of estrogen modulators through classical and space modeling approaches: Exploration of bridged-cyclic compounds with diarylethylene linkage

The dimensional expansion in the research domain of Selective Estrogen Receptor (ER) Modulators (SERM) has been driven by discovering molecules with improved endocrine profiles that might be safer and valuable drug candidates for treating variety of estrogen-linked pathologies. Desirable tissue selectivity may result from the unique structural characteristics of a ligand that take advantage of differences in diversities of cell specific factors. The recent discovery of a second ER has provoked the search for ligands which are selective for either the classical ER or newer subtypes. Libraries of compounds, both synthetic and natural are being screened globally for finding ideal SERMs and investigating pharmacophore patterns for apprehending tissue selective parameters. Diverse series of selective synthetic analogs have been developed with high relative binding affinities to the ER as comparable to 17β-estradiol and extensive data sets of phytoestrogens have also been screened for selective binding at the ER surfaces. The successful synthesis, exploration of natural resources and biological testing of SERMs are emerging as vital tools for apprehending the differences in structure and biological functions of ER subtypes as well as for deducing pharmacophore maps of estrogenic analogs through application of virtual molecular modeling applications. Several approaches in calculating ligand-binding affinities have been used over the past decade, ranging from molecular field analysis studies to protein-based methods using empirical scoring functions. One of the most promising areas in present day computational chemistry that has further aided the understanding of mechanistic aspects of estrogenic activity, is the characterization of molecular properties and bio-activities by means of structure-based descriptors generated from theoretical improvement and computational applications that eventually lead to construction of quantitative SAR related to molecular features by statistical procedures. Consequently, this paper overviews the properties investigated towards explaining tissue selectivity of estrogens and structural homology patterns of active analogs on precision based In silico approaches. This review also takes into account some our ongoing research efforts in this area that have contributed significant findings. © 2006 Bentham Science Publishers Ltd.

Current Computer-Aided Drug Design

Molecular modeling studies of estrogen receptor modulators

Considering the worth of developing non-steroidal estrogen analogues, the present research explores the pharmacophores of 1-trifluoromethyl-1,2,2- triphenylethylenes (Fig. 1) for post-coital antifertility activity using electrotopological state atom (E-state) index. The study shows the efficacy of E-state index in developing statistically acceptable model, which explains the electronic environment and topological states of different atoms in a molecule. The exploration concluded that phenyl ring attached to an ethylenic moiety, para substitution by nucleophilic group on the phenyl ring and presence of strong electronegative group as the 4th substituent on the 1st carbon of the ethylenic moiety might be crucial for activity. © 2003 Elsevier Ltd. All rights reserved.

Bioorganic and Medicinal Chemistry Letters

Predicting pharmacophore signals for post-coital antifertility activity of 1-trifluoromethyl-1,2,2-triphenylethylene derivatives: A statistical approximation using E-state index

Considering the importance of developing selective COX-2 inhibitors, the present paper explores selectivity requirements for COX-2 versus COX-1 binding of 3,4-diaryloxazolones using electrotopological state (E-state) index. The study also shows the utility of E-state index in developing statistically acceptable model having direct physicochemical significance: electron density distribution of different atoms of the oxazolone ring and attached two phenyl rings are important for the selective binding with COX-2 over COX-1. Moreover, the use of indicator variable shows that presence of ortho R1 substituent (except fluoro) on the N3-phenyl ring decreases COX-2 selectivity. Further, an amino substituent at R2 position (i.e., sulfonamide compound) is favorable for increasing COX-2 selectivity when the R3 position is unsubstituted. © 2003 Elsevier Ltd. All rights reserved.

Journal	Biological and Pharmaceutical Bulletin
Publisher	PHARMACEUTICAL SOC JAPAN
ISSN	0918-6158
Open Access	No