Quantitative structure–activity relationship of organophosphate compounds based on molecular interaction fields descriptors

By using multi-block partial least-squares (MBPLS) method, quantitative structure–activity relationship (QSAR) between 35 organophosphate compounds (OP) and their 24 h acute toxicities towards the housefly (Musca nebulo L.) was built on the molecular interaction fields (MIF) descriptors, which were obtained with O, N and DRY as probes, and then normalised with block unscaled weights (BUW) technique. The best QSAR model had 8 principal components, with the coefficient of determination R2 = 0.995 and that of leave-one-out cross-validation Q2 = 0.865, and the corresponding standard deviation of error 0.076 and 0.361, respectively. Block importance in the prediction (BIP) for O, N and DRY probe were 1.030, 0.962 and 1.007, respectively. Contour map of variable coefficients showed that hydrogen bonding between the O atom in PO and the NH groups in acetylcholinesterase (AChE) played an important role in the interaction between OP and AChE. Meanwhile, the hydrophobicity of OP also had significant contribution. QSAR based on the MIF descriptors could be a potential means to interpret the mechanisms of ligand–receptor interaction when the receptor was well known.

► Multi-block partial least-squares with block unscaled weights scaling method was applied in building QSAR models.
► The hydrophobicity and hydrogen bond acceptor and donor played an important role in the interaction of OP and AChE.
► The 3D-QSAR based on MIF descriptors could characterise various potential fields surrounding a ligand.
► The special 3D-QSAR could interpret the possible interaction mechanisms between active sites and the ligand.