Computers in Biology and Medicine 38 (2008) 1056 – 1067 www.intl.elsevierhealth.com/journals/cobm Analysis of binding residues between scorpion neurotoxins and D2 dopamine receptor: A computational docking study C. Sudandiradoss, C. George Priya Doss, R. Rajasekaran, Rituraj Purohit, K. Ramanathan, Rao Sethumadhavan ∗ Bioinformatics Division, School of Biotechnology, Chemical and Biomedical Engineering, Vellore Institute of Technology University, Vellore 632014, Tamil Nadu, India Received 18 September 2007; accepted 5 August 2008 Abstract We report the results on the computation of binding affinity, electrostatic free energies, contact free energies, secondary structures, stabilization centers and stabilizing residues of binding residues during the molecular docking of selected scorpion neurotoxins with D2 dopamine receptor. All the scorpion neurotoxins showed a good and satisfactory docking with the D2 receptor molecule except one neurotoxin 2SN3. We computed multiple alignment studies, solvent accessibility calculations, secondary structure analysis, stabilization centers and stabilizing residues before and after the docking process. Overall, we emphasize that the results obtained in this work will be very helpful in further enhancement of understanding the research on modeling and drug design with respect to the D2 dopamine receptor.  2008 Elsevier Ltd. All rights reserved. Keywords: D2 dopamine receptor; Scorpion neurotoxins; Molecular docking; Binding affinity; Molecular modeling; Stabilization centers; Stabilizing residues 1. Introduction Dopamine receptors play a critical role in cellular signal- ing processes responsible for information transfer and neuron’s function in the nervous system [1,2]. They are involved in neu- rological signaling and play important roles in cognitive and emotional functions and neurological disorders [3]. Dopamine receptors belong to the superfamily of G-protein coupled re- ceptors (GPCRs), and to date there are five reported sequences for the human dopamine receptors with multiple isoforms for each [1]. Nearly 30% of total drug sales and prescriptions are directed at GPCRs [4], making them the most highly desired drug discovery targets by the pharmaceutical industry [5–7]. Among the GPCRs, the dopamine receptors are ideal targets for treating schizophrenia and Parkinson’s disease [8]. There- fore, the need to solve the high resolution 3D structure of this class of integral membrane proteins to enable structure- based drug design is an important problem in structural biology. But till today the 3D structures of dopamine receptors are not ∗ Corresponding author. Tel.: +91 4162202522; fax: +91 4162243092. E-mail address: rsethumadhavan@vit.ac.in (R. Sethumadhavan). 0010-4825/$ - see front matter  2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.compbiomed.2008.08.003 available. This lack of structures is because the dopamine re- ceptors are bound to the membrane, making it difficult to ex- press in sufficient quantities for crystallization. Five dopamine receptors have been identified and classified as D1-like (D1 dopamine receptor and D5 dopamine receptor) and D2-like (D2 dopamine receptor, D3 dopamine receptor and D4 dopamine receptor) based on their similarities to pharma- cologically defined sites identified in brain tissue [9–11]. All of them share a high degree of homology to bovine rhodopsin [12], the only experimental 3D structure available for long time among the GPCRs. However, a more recent report on hu- man beta2 adrenergic G-protein coupled receptor [13] shows the highest degree of homology to D2 dopamine receptor than bovine rhodopsin. Since, the D2 dopamine receptor is more widespread than the other dopamine receptors and tends to show up in greater density [9,11], the development of improved remedies would be significantly enhanced with the availability of the 3D structure for the D2 dopamine receptor. Although there are well known organic molecules which can act against D2 dopamine receptor, we have used scorpion neurotoxins as a protein based drug template against D2 dopamine receptor using a computational docking method. Scorpion venoms and