Investigations and design of pyridine-2-carboxylic acid thiazol-2-ylamide analogs as methionine aminopeptidase inhibitors using 3D-QSAR and molecular docking

TY - JOUR

T1 - Investigations and design of pyridine-2-carboxylic acid thiazol-2-ylamide analogs as methionine aminopeptidase inhibitors using 3D-QSAR and molecular docking

AU - Hauser, Alexander Sebastian

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Methionine amino peptidases (MetAPs) are metalloproteases that remove co-translational N-terminal methionine from nascent polypeptide chains. Due to their essential role in protein synthesis, MetAPs are considered as potential targets for antibacterial drugs. In the present work, three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of pyridine-2-carboxylic acid thiazol-2-ylamide-based MetAP inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models were developed using 30 training set molecules. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients (q 2) of 0.799 and 0.704 and conventional correlation coefficients (r 2) of 0.989 and 0.954, respectively. These inhibitors were docked into MetAP active site. The CoMFA and CoMSIA field contour maps correlate well with the structural characteristics of the binding pocket of MetAP active site. Using the knowledge of structure–activity relationship and receptor–ligand interactions from 3D-QSAR model and the docked complexes, four new pyridine-2-carboxylic acid thiazol-2-ylamide analogs were designed. These analogs exhibit significantly better predicted activity than the reported molecules. The present work has implications for the development of novel antibiotics as potent MetAP inhibitors.

AB - Methionine amino peptidases (MetAPs) are metalloproteases that remove co-translational N-terminal methionine from nascent polypeptide chains. Due to their essential role in protein synthesis, MetAPs are considered as potential targets for antibacterial drugs. In the present work, three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of pyridine-2-carboxylic acid thiazol-2-ylamide-based MetAP inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models were developed using 30 training set molecules. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients (q 2) of 0.799 and 0.704 and conventional correlation coefficients (r 2) of 0.989 and 0.954, respectively. These inhibitors were docked into MetAP active site. The CoMFA and CoMSIA field contour maps correlate well with the structural characteristics of the binding pocket of MetAP active site. Using the knowledge of structure–activity relationship and receptor–ligand interactions from 3D-QSAR model and the docked complexes, four new pyridine-2-carboxylic acid thiazol-2-ylamide analogs were designed. These analogs exhibit significantly better predicted activity than the reported molecules. The present work has implications for the development of novel antibiotics as potent MetAP inhibitors.

KW - Former Faculty of Pharmaceutical Sciences

KW - Molecular docking

KW - 3D-QSAR

KW - CoMSIA CoMFA

KW - CoMFA

U2 - 10.1007/s00044-014-0950-z

DO - 10.1007/s00044-014-0950-z

M3 - Journal article

SN - 1054-2523

VL - 23

SP - 3861

JO - Medicinal Chemistry Research

JF - Medicinal Chemistry Research

IS - 8

ER -