Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc(1): a molecular basis for drug design

Nayak, Susanta K and Mallik, Srijita Basu and Kanaujia, Shankar Prasad and Sekar, Kanagaraj and Ranganathan, KR and Ananthalakshmi, V and Jeyaraman, G and Saralaya, SS and Rao, Sundararaja K and Shridhara, K and Nagarajan, K and Row, Guru Tayur N (2013) Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc(1): a molecular basis for drug design. In: CrystEngComm, 15 (24). pp. 4871-4884.

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Abstract

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 protein-inhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular O-H center dot center dot center dot O hydrogen bond dimer motifs supported by surrogate weak interactions including C-H center dot center dot center dot O and C-H center dot center dot center dot Cl hydrogen bonds. The docking results of these molecules with cytochrome bc(1) show preferences to form N-H center dot center dot center dot O, O-H center dot center dot center dot O and O-H center dot center dot center dot Cl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of protein-ligand 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.

Item Type:	Journal Article
Publication:	CrystEngComm
Publisher:	Royal Society of Chemistry
Additional Information:	Copyright of this article belongs to Royal Society of Chemistry.
Department/Centre:	Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited:	11 Jul 2013 11:13
Last Modified:	11 Jul 2013 11:13
URI:	http://eprints.iisc.ac.in/id/eprint/46830

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