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An ab initio quantum mechanical drug designing procedure: application to the design of balanced dual ACE/NEP inhibitors

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Abstract

This article describes in a sequential fashion how ab initio quantum mechanical methods can be applied to study the pharmacophoric features of drugs. It also describes how accurate drug–receptor interaction calculations can guide the careful design of balanced dual inhibitors, which form an important class of second generation drugs. As an example, the authors have chosen balanced inhibitors of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) as modern antihypertensive drugs. A unified, accurate, in silico design approach is presented, encompassing all steps from pharmacophore derivation to complete understanding of mechanistic aspects leading to drug design.

Lisinopril docked in angiotensin converting enzyme (ACE) model

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Acknowledgments

We gratefully acknowledge financial support by DST (Department of Science and Technology, New Delhi) project no. SR/S1/PC-06/2004. One of us (N. K. Rao) gratefully acknowledges DST for the Senior Research Fellowship.

Author information

Correspondence to Arpita Yadav.

Electronic supplementary material

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Suppl. 1

Different optimised conformations of Enalaprilat (DOC 259 kb)

Suppl. 2

Bioactive Enalaprilat docked in ACE active site model (best orientation) (DOC 614 kb)

Suppl. 3

Bioactive Enalaprilat docked in ACE active site model (different orientation) (DOC 394 kb)

Suppl. 4

(DOC 25 kb)

Suppl. 5

(WMV 1536 kb)

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Rao, N.K., Yadav, A. & Kumar Singh, S. An ab initio quantum mechanical drug designing procedure: application to the design of balanced dual ACE/NEP inhibitors. J Mol Model 15, 1447–1462 (2009) doi:10.1007/s00894-009-0500-7

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Keywords

  • Ab initio
  • Drug–receptor interaction
  • ACE/NEP dual inhibitor
  • ACE receptor model
  • Modern antihypertensive