PMID- 23545333
OWN - NLM
STAT- MEDLINE
DCOM- 20131227
LR  - 20211203
IS  - 1873-4243 (Electronic)
IS  - 1093-3263 (Linking)
VI  - 42
DP  - 2013 May
TI  - Pharmacophore modeling, homology modeling, and in silico screening reveal 
      mammalian target of rapamycin inhibitory activities for sotalol, glyburide, 
      metipranolol, sulfamethizole, glipizide, and pioglitazone.
PG  - 39-49
LID - S1093-3263(13)00043-0 [pii]
LID - 10.1016/j.jmgm.2013.02.009 [doi]
AB  - Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and member of 
      the PI3K-related kinase (PIKK) family. It plays a central role in integrating 
      signals from metabolism, energy homeostasis, cell cycle, and stress response. 
      Aberrant PI3K/mTOR activation is commonly observed in diseases such as cancer, 
      diabetes and Alzheimer's disease. Accordingly, we developed common feature 
      binding hypotheses for a set of 6 potent mTOR antagonists. The generated models 
      were validated using receiver operating characteristic (ROC) curve analyses. To 
      gain better insight into ligand-mTOR interactions, a homology model for the 
      kinase domain of mTOR was built using the crystallographic structure of PI3Kgamma as 
      template. The optimal pharmacophore model was further improved based on detailed 
      docking studies of potent training compound in the homology model. The modified 
      binding model was employed as 3D search query to screen our in-house-built 
      database of established drugs. Subsequent in vitro screening of captured hits 
      showed that six of them have submicromolar to low micromolar bioactivities, 
      namely, glyburide, metipranolol, sulfamethizole, glipizide, pioglitazone, and 
      sotalol.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Khanfar, Mohammad A
AU  - Khanfar MA
AD  - Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, 
      University of Jordan, Amman 11942, Jordan.
FAU - AbuKhader, Majed M
AU  - AbuKhader MM
FAU - Alqtaishat, Saja
AU  - Alqtaishat S
FAU - Taha, Mutasem O
AU  - Taha MO
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130313
PL  - United States
TA  - J Mol Graph Model
JT  - Journal of molecular graphics & modelling
JID - 9716237
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Thiazolidinediones)
RN  - 25W8454H16 (Sulfamethizole)
RN  - A6D97U294I (Sotalol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - SX6K58TVWC (Glyburide)
RN  - X39AL81KEB (Metipranolol)
RN  - X4OV71U42S (Pioglitazone)
RN  - X7WDT95N5C (Glipizide)
SB  - IM
MH  - Adrenergic beta-Antagonists/*pharmacology
MH  - Amino Acid Sequence
MH  - Anti-Infective Agents/*pharmacology
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Glipizide/pharmacology
MH  - Glyburide/pharmacology
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology
MH  - Metipranolol/pharmacology
MH  - Models, Molecular
MH  - Molecular Docking Simulation
MH  - Phosphatidylinositol 3-Kinases/*chemistry
MH  - Pioglitazone
MH  - Quantitative Structure-Activity Relationship
MH  - ROC Curve
MH  - Sequence Alignment
MH  - Sotalol/pharmacology
MH  - Sulfamethizole/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Thiazolidinediones/pharmacology
EDAT- 2013/04/03 06:00
MHDA- 2013/12/29 06:00
CRDT- 2013/04/03 06:00
PHST- 2012/12/20 00:00 [received]
PHST- 2013/02/21 00:00 [revised]
PHST- 2013/02/24 00:00 [accepted]
PHST- 2013/04/03 06:00 [entrez]
PHST- 2013/04/03 06:00 [pubmed]
PHST- 2013/12/29 06:00 [medline]
AID - S1093-3263(13)00043-0 [pii]
AID - 10.1016/j.jmgm.2013.02.009 [doi]
PST - ppublish
SO  - J Mol Graph Model. 2013 May;42:39-49. doi: 10.1016/j.jmgm.2013.02.009. Epub 2013 
      Mar 13.