Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc1: a molecular basis for drug designElectronic supplementary information (ESI) available: The synthesis procedures adopted and melting points (Table S1), Fig. S1S6. CCDC 749765749772. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ce40336j

• Main Authors: Nayak, Susanta K, Mallik, Srijita Basu, Kanaujia, Shankar Prasad, Sekar, Kanagaraj, Ranganathan, K. R, Ananthalakshmi, V, Jeyaraman, G, Saralaya, S. S, Rao, K. Sundararaja, Shridhara, K, Nagarajan, K, Row, Tayur N. Guru
• Format: Article
• Language: English
• ISSN: 1466-8033
• DOI: 10.1039/c3ce40336j

Crystal structure of trans -atovaquone (antimalarial drug), its polymorph and its stereoisomer ( cis ) along with five other derivatives with different functional groups have been analyzed. Based on the conformational features of these compounds and the characteristics of the nature of intermolecular interactions, valuable insights into the atomistic details of proteininhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular OHO hydrogen bond dimer motifs supported by surrogate weak interactions including CHO and CHCl hydrogen bonds. The docking results of these molecules with cytochrome bc 1 show preferences to form NHO, OHO and OHCl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of proteinligand docking reported earlier based on mimicking experimental binding results of stigmatellin with cytochrome bc 1 . The significance of subtle energy factors controlled by weak intermolecular interactions appears to play a major role in drug binding. Atovaquone binding to the ubiquinol oxidation pocket of the yeast cytochrome bc 1 complex occurs through hydrogen bonds as shown from X-ray diffraction and docking studies.