Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1, 4-naphthoquinones through molecular modelling

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.

Molecular docking study of 3,6 bis(3’substituted propoxy) and 3,6 bis (5’substituted pentyloxy) xanthone derivatives as PGHS- 2 inhibitors.

The primary effect of the NSAIDs is to inhibit cyclooxygenase (COX or prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the COX enzyme have been described, COX-1 and COX-2. Identification of this cyclooxygenase-2 (COX-2) isoform resulted in the development of selective COX-2 inhibitors, with the hope of producing a safer analgesic and anti-inflammatory agent. The principal benefit with the selective COX-2 inhibitors is the production of comparable analgesia and antiinflammatory effects to the nonselective NSAIDs, but with fewer symptomatic gastric and duodenal ulcers and a decrease in gastrointestinal symptoms. In the present work, twelve novel series of xanthone derivatives (A1-A6 and B1-B6) were allowed to dock against PGHS-2(prostaglandin endoperoxide synthase-2) protein (PDB ID: 3LN1) to evaluate their comparative efficacy in terms of docking performance. The results are discussed on the basis of binding energy value.

Synthesis and anticancer activity study of diosgenin derivatives / 中国药学杂志

OBJECTIVE: To synthesize diosgenin derivatives and investigate their anti-tumor activities in vitro. METHODS: Designed and docked by AutoDock4.2, a series of diosgenin derivatives were selectively prepared from diosgenin. Their anti-tumor activities in vitro were evaluated for human malignant melanoma A375 cells, human lung adenocarcinoma A549 cells, human hepatoma HepG-2 cells and human myeloid leukemia K562 cells by MTT assay. RESULTS: Twelve novel compounds were synthesized and the basic structures were characterized by 1H-NMR and 13C-NMR. MTT assay showed that most of the diosgenin derivatives exhibited some anti-tumor activities. CONCLUSION: Most of the synthesized compounds had certain antitumor activity and showed no or little toxicity against the normal cells. Copyright 2012 by the Chinese Pharmaceutical Association.