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ACS chemical neuroscience v.8 no.1, 2017년, pp.147 - 154   SCIE
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Technically Extended MultiParameter Optimization (TEMPO): An Advanced Robust Scoring Scheme To Calculate Central Nervous System Druggability and Monitor Lead Optimization

Ghose, Arup K. Ott, Gregory R. Hudkins, Robert L.
  • 초록  

    At the discovery stage, it is important to understand the drug design concepts for a CNS drug compared to those for a non-CNS drug. Previously, we published on ideal CNS drug property space and defined in detail the physicochemical property distribution of CNS versus non-CNS oral drugs, the application of radar charting (a graphical representation of multiple physicochemical properties used during CNS lead optimization), and a recursive partition classification tree to differentiate between CNS- and non-CNS drugs. The objective of the present study was to further understand the differentiation of physicochemical properties between CNS and non-CNS oral drugs by the development and application of a new CNS scoring scheme: Technically Extended MultiParameter Optimization (TEMPO). In this multiparameter method, we identified eight key physicochemical properties critical for accurately assessing CNS druggability: (1) number of basic amines, (2) carbon–heteroatom (non-carbon, non-hydrogen) ratio, (3) number of aromatic rings, (4) number of chains, (5) number of rotatable bonds, (6) number of H-acceptors, (7) computed octanol/water partition coefficient (AlogP), and (8) number of nonconjugated C atoms in nonaromatic rings. Significant features of the CNS-TEMPO penalty score are the extension of the multiparameter approach to generate an accurate weight factor for each physicochemical property, the use of limits on both sides of the computed property space range during the penalty calculation, and the classification of CNS and non-CNS drug scores. CNS-TEMPO significantly outperformed CNS-MPO and the Schrödinger QikProp CNS parameter (QP_CNS) in evaluating CNS drugs and has been extensively applied in support of CNS lead optimization programs. Graphic Abstract ACS Electronic Supporting Info


  • 주제어

    Central nervous system (CNS) .   CNS-TEMPO .   non-CNS .   CNS drug discovery .   CNS lead optimization .   non-CNS drug discovery .   non-CNS lead optimization .   multiparameter optimization.  

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