Exploring structural requirements of aurone derivatives as antimalarials by validated DFT-based QSAR, HQSAR, and COMFA–COMSIA approach

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• 作者：Nilanjan Adhikari (1)
  Amit Kumar Halder (1)
  Chanchal Mondal (1)
  Tarun Jha (1)
  
• 关键词：Antimalarial ; Aurone derivative ; DFT ; HQSAR ; CoMFA ; CoMSIA
• 刊名：Medicinal Chemistry Research
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：22
• 期：12
• 页码：6029-6045
• 全文大小：
• 作者单位：Nilanjan Adhikari (1)
  Amit Kumar Halder (1)
  Chanchal Mondal (1)
  Tarun Jha (1)
  
  1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032, India
  
• ISSN：1554-8120

文摘

Chloroquine resistance is nowadays a great problem in malaria. Aurone derivatives were effective against chloroquine resistant parasite. Validated density functional theory (DFT)-based chemometric modeling, hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity analysis (CoMSIA) studies were conducted on 35 aurone derivatives having antimalarial activity. 2D-QSAR models were developed on the training sets by Y-based ranking method. This model was validated on 50 pairs of the test and the training sets by k-Means cluster analysis method. HQSAR, CoMFA, and CoMSIA models were validated by standard techniques and each method validates the DFT-based 2D-QSAR study and in turn validates the earlier observed structural activity relationship data as well as each other. DFT-based 2D-QSAR model suggests that the increase of Mulliken charge at C14 and HOMO density located on C11 may be conducive to antimalarial activity. Ethyl group attached to C14 and the increase of the value of chemical potential may be beneficial for antimalarial activity. Methoxy fragment is important for better antimalarial activity by HQSAR study. CoMFA analysis shows a favorable steric green region is located near C14 whereas the unfavorable yellow region is far away from C14. A large blue region located near C14 indicates the positively charged groups are favorable at this position. CoMSIA steric features correlates well with the CoMFA steric features. CoMSIA study suggests the bulky hydrophobic substitution at C14 is necessary for antimalarial activity. These results may be utilized to obtain potential antimalarial molecules.