Journal of Molecular Modeling

, Volume 18, Issue 2, pp 569–582 | Cite as

Multiple receptor conformation docking and dock pose clustering as tool for CoMFA and CoMSIA analysis – a case study on HIV-1 protease inhibitors

Original Paper


Multiple receptors conformation docking (MRCD) and clustering of dock poses allows seamless incorporation of receptor binding conformation of the molecules on wide range of ligands with varied structural scaffold. The accuracy of the approach was tested on a set of 120 cyclic urea molecules having HIV-1 protease inhibitory activity using 12 high resolution X-ray crystal structures and one NMR resolved conformation of HIV-1 protease extracted from protein data bank. A cross validation was performed on 25 non-cyclic urea HIV-1 protease inhibitor having varied structures. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were generated using 60 molecules in the training set by applying leave one out cross validation method, rloo2 values of 0.598 and 0.674 for CoMFA and CoMSIA respectively and non-cross validated regression coefficient r2 values of 0.983 and 0.985 were obtained for CoMFA and CoMSIA respectively. The predictive ability of these models was determined using a test set of 60 cyclic urea molecules that gave predictive correlation (rpred2) of 0.684 and 0.64 respectively for CoMFA and CoMSIA indicating good internal predictive ability. Based on this information 25 non-cyclic urea molecules were taken as a test set to check the external predictive ability of these models. This gave remarkable out come with rpred2 of 0.61 and 0.53 for CoMFA and CoMSIA respectively. The results invariably show that this method is useful for performing 3D QSAR analysis on molecules having different structural motifs.


Schematic representation of the multiple receptor conformation docking, clustering and 3D QSAR. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) analysis is an exceptional tool for understanding the structure activity relations of molecules towards their biological activities. Receptor binding conformation of the molecule gives an added advantage to understand ligand receptor interactions required for bioactivity. There are different methods employed for obtaining the receptor based alignment of the molecules, but this method is limited to molecules having common substructure. Here we describe the new approach of multiple receptors conformation docking (MRCD) and clustering of dock poses that allows seamless incorporation of receptor binding conformation of the molecules on wide range of molecules with varied structural scaffold.


AIDS (acquired immunodeficiency syndrome) CoMFA (Comparative molecular field analysis) CoMSIA (Comparative molecular similarity indices analysis) HIV- 1 (Human immunodeficiency virus type1) MRCD (Multiple receptor conformation docking) PLS (partial least square) analysis PR (aspartic protease) 

Supplementary material

894_2011_1048_MOESM1_ESM.txt (6 kb)
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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Chemistry, Nizam CollegeOsmania UniversityHyderabadIndia

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