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CoMFA, CoMSIA, and Docking Studies on Thiolactone‐Class of Potent Anti‐malarials: Identification of Essential Structural Features Modulating Anti‐malarial Activity
Author(s) -
Roy Kuldeep K.,
Bhunia Shome S.,
Saxena Anil K.
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01158.x
Subject(s) - stereochemistry , docking (animal) , protein data bank (rcsb pdb) , chemistry , active site , thiolactone , lead compound , structure–activity relationship , rational design , combinatorial chemistry , enzyme , biochemistry , in vitro , biology , medicine , nursing , genetics
The integrated ligand‐ and structure‐based drug design techniques have been applied on a homogeneous dataset of thiolactone‐class of potent anti‐malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum . Developed CoMFA ( q 2 = 0.716) and CoMSIA ( q 2 = 0.632) models well explained structure–activity variation in both the training (CoMFA R 2 = 0.948 & CoMSIA R 2 = 0.849) and test set (CoMFA R 2 pred = 0.789 & CoMSIA R 2 pred = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high‐resolution (2.35 Å) structure of FabB‐TLM binary complex (PDB‐ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H‐bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein–ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone‐class of compounds that could furnish improved anti‐malarial activity.