title: CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity.
abstract: 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.
authors.affiliation: Division of Medicinal and Process Chemistry, Central Drug Research Institute CSIR, Lucknow-226001, India.
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Shome S
authors.initials: SS
authors.lastname: Bhunia
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D013876:Thiophenes; C035068:thiolactomycin