The cytochrome-P450 (CYP) complex aromatase is the rate-limiting step in the production of endogenous estrogen. This synthesis can be controlled with aromatase inhibitor (AI). Different types of AIs are under extensive study for use in the treatment of advanced breast cancer in postmenopausal patients. In view of such significance, the present study explored the pharmacophores of benzofuran derivatives containing pyridine, imidazole and triazole substituents for inhibiting selective aromatase enzyme, CYP19 activity. Implementing classical QSAR (R2=0.858, Q2=0.737, s=0.349, R 2 test=0.839) and space modeling (R2=0.908, Δcost=179.138, rmsd=1.235, R2 test=0.867) approaches, it has been explored that molecular hydrophobicity, presence of suitable ring substituent and hydrogen bond acceptors are the crucial key features of the benzofuran scaffold for imparting CYP19 inhibitory activity. Moreover steric properties of the molecule have influence on the activity. © 2009 Bentham Science Publishers Ltd.

ACHINTYA SAHA

Chemical Technology

S NAGAR

MD A ISLAM

S DAS

A MUKHERJEE

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

Pharmacophore Searching of Benzofuran Derivatives for Selective CYP19 Aromatase Inhibition

Letters in Drug Design and Discovery

Aromatase is an enzyme that catalyzes the final step in the conversion of androgen to estrogen. It has become an attractive target for the treatment of estrogen responsive breast cancer. The study has been focused on designing aromatase inhibitors (AIs) that can. be selected as probable drug candidate for the treatment of breast cancer. In the present study, long chain diarylalkyl-imidazole and -triazole scaffolds have been considered for exploring pharmacophores as potent AIs using QSAR (Quantitative SAR) and pharmacophore mapping studies. The model generated in linear free energy QSAR study (R 2 = 0.905, Q2= 0.885, R2pred(ts) = 0.763) showed the importance of hydrophobicity, size and shape of the molecule, van der Waals surface and hydrogen atom contribution influence the activity. 3D QSAR of comparative molecular field analysis (CoMFA, R2= 0.921, Q2 = 0.741, R2pred(ts)= 0.583) showed that steric and electrostatic features along with hydrophobicity and electronic charge contribution at C4 (Fig. 1) influence on the inhibitory activity. Comparative molecular similarity analysis (CoMSIA, R2 = 0.874, Q2 = 0.716, R2pred(ts) = 0.591) study adjudged the presence of steric, electrostatic and hydrophobic fields together with hydrogen bond (HB) donor and acceptor play significant role in inhibitory activity to aromatase enzyme. Further pharmacophore mapping study (Q2 = 0.947, Δcost = 113.171, R2pred(ts) = 0.857) suggested that presence of HB acceptor, hydrophobicity with aromatic ring, and the importance of steric contribution influence on the activity. The critical distances among the features are also important for the inhibitor activity. © 2010 Wiley Periodicals, Inc.

Journal of Computational Chemistry

Modeling of diarylalkyl-imidazole and diarylalkyl-triazole derivatives as potent aromatase inhibitors for treatment of hormone-dependent cancer

Aromatase inhibition is an attractive strategy for the treatment of hormone-dependent breast cancer. Quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies are performed on benzcyclo- pentane/hexane derivatives to generate statistically significant models. Linear free energy QSAR model (R2 = 0.874, Q2 = 0.824, Rpred2=0.757) showed the importance of hydrophobicity and atomic charge functionality of the molecule for the activity. 3D QSAR models generated with molecular field (CoMFA, R2 = 0.973, Q2 = 0.702, Rpred2=0.612) and similarity analysis (CoMSIA, R2 = 0.976, Q 2 = 0.803, Rpred2=0.706) studies indicated the importance of electrostatic and steric fields along with hydrophobicity of the molecule as important features for inhibiting aromatase enzyme. Further pharmacophore space modeling study (Q2 = 0.845, Rpred2=0.648) confirmed that molecular hydrophobicity plays key role for aromatase inhibition. The structure-function characterization is adjudged in the active site of the target (3EQM). QSAR modeling and pharmacophore mapping have been explored to investigate the structural pattern of benzcyclo hexane/pentane derivative for inhibition of aromatase (CYP19) enzyme. © 2010 Elsevier Masson SAS. All rights reserved.

Journal	Letters in Drug Design and Discovery
Publisher	BENTHAM SCIENCE PUBL LTD
ISSN	1570-1808
Open Access	No