CoMFA AND CoMSIA STUDIES ON A SET OF BENZYL PIPERAZINES, PIPERADINES, PYRAZINOPYRIDOINDOLES, PYRAZINOISOQUINOLINES AND SEMI RIGID ANALOGS OF DIPHENHYDRAMINE |
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Authors: | Stuti Gaur Philip Prathipati Mridula Saxena Anil K Saxena |
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Institution: | (1) Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, India |
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Abstract: | 3D QSAR studies using CoMFA and CoMSIA have been carried out using 40 antihistamines H1 belonging to substituted benzyl piperazines/piperidines,
pyrazinopyridoindoles, pyrazinoisoquinolines and semirigid analogs of diphenhydramine. Chemical feature based pharmacophoric
alignments were used to develop models using different fields viz. tripos standard, hydrogen bonding, parabolic indicator
in the case of CoMFA and steric, electrostatic, donor, acceptor, hydrophobic, donor and acceptor, steric and electrostatic
in the case of CoMSIA. All the eleven derived models were further optimized using the PLS region focusing tool to increase
the model resolution which led to eleven more models. The removal of two outliers led to statistically significant models.
The best CoMFA models was the one developed using the (region focused) CoMFA parabolic fields (r2=0.988,q2 LOO = 0.596, q2 Leave 10% out =0.592, q2 Leave 30% out = 0.606) and the best CoMSIA model was the one with (region focused) CoMSIA steric fields (r2=0.989, q2 LOO =0.74, q2 Leave 10% out = 0.726, q2 Leave 30% out =0.74). |
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