Development and validation of a modular, extensible docking program: DOCK 5

Moustakas, Demetri T.; Lang, P. Therese; Pegg, Scott C.‐H.; Pettersen, Eric F.; Kuntz, Irwin D.; Brooijmans, Natasja; Rizzo, Robert C.

doi:10.1007/s10822-006-9060-4

Cited by 385 publications

(305 citation statements)

References 45 publications

Supporting

Mentioning

301

Contrasting

Unclassified

Order By: Relevance

“…Preliminary docking calculations with AutoDock [22], DOCK [23], eHiTS [24], FlexX [25], GOLD [26], and LigandFit to reproduce the pose of the bound leucine in the leucine transporter LeuT Aa showed that LigandFit was the best software to reproduce the orientation of the leucine in the active site and especially the interaction of the Leucine carboxyl group with the sodium atom Na1. Table 1).…”

Section: Docking Of Ligandsmentioning

confidence: 99%

Generation of a 3D model for human GABA transporter hGAT-1 using molecular modeling and investigation of the binding of GABA

Wein

Wanner

2009

J Mol Model

View full text Add to dashboard Cite

A three-dimensional model of the human Na+/Cl--dependent y-aminobutyric acid (GABA) transporter hGAT-1 was developed by homology modeling and refined by subsequent molecular modeling using the crystal structure of a bacterial homologue leucine transporter from Aquifex aeolicus (LeuTAa) as the template. Protein structure quality checks show that the resulting structure is particular suited for the analysis of the substrate binding pocket and virtual screening experiments. Interactions of GABA and the substrate binding pocket were investigated using docking studies. The difference of 6 out of 13 substrate interacting side chains between hGAT-1 and LeuTAa lead to the different substrate preference which can be explained using our three-dimensional model of hGAT-1. In particular the replacement of serine 256 and isoleucine 359 in LeuTAa with glycine and threonine in hGAT-1 seems to facilitate the selection of GABA as the main substrate by changing the hydrogen bonding pattern in the active site to the amino group of the substrate. For a set of 12 compounds flexible docking experiments were performed using LigandFit in combination with the Jain scoring function. With few exceptions the obtained rank order of potency was in line with experimental data. Thus, the method can be assumed to give at least a rough estimate of the potency of potential of GABA uptake inhibitors Response to Reviewers: Reviewer #2: Obviously, no PME was used for Gromacs minimization, which is not state-of-the-art.Answer to reviewer: We are very thankful for this suggestion and have repeated the procedure of minimizing the initial protein structure using PME. In addition, we have heated the system using a simulated annealing approach in order to let the protein structure adopt better to GABA as the ligand. The differences in the resulting structure compared to the original structure are very small but, of course, in the paper we report the structure modelled with PME and after simujlated annealing.Reviewer #2:I doubt that LigandFit is the only one of the docking codes mentioned which is able to cope with the sodium-carboxylate-interaction mentioned in the text. the pose of the bound leucine in the leucine transporter LeuTAa showed that LigandFit was the best software to reproduce the orientation of the leucine in the active site and especially the interaction of the Leucine carboxyl group with the sodium atom Na1." In order to select the best-suited docking software for our needs, we have done preliminary docking calculations using the X-Ray structure of LeuTaa. These calculations showed clearly that LigandFit was best suited to reproduce especially the important interaction of the carboxylate to the sodium atom (Na1). Even with modifications in parameter files suggested by support people for FlexX and GOLD, LigandFit performed better in this very special case! And, differrent to the Pallo publication we don't need to introduce the carboxy-sodium interaction as restraint for our calculations! Reviewer #2: The much more extens...

show abstract

Section: Docking Of Ligandsmentioning

confidence: 99%

Generation of a 3D model for human GABA transporter hGAT-1 using molecular modeling and investigation of the binding of GABA

Wein

Wanner

2009

J Mol Model

View full text Add to dashboard Cite

show abstract

“…Virtual screening of the OR4M1 binding pocket: The pocket identified in the 3D OR4M1 model was used as a target for virtual screening of small molecule compounds. A set of ~5 million lead-like compounds (Teague et al, 1999), derived from the ZINC library of commercially available compounds (Irwin and Shoichet, 2005), was docked into the binding site using program DOCK version 6.5 (Moustakas et al, 2006). Lead-like compounds were selected to facilitate optimization of validated hits.…”

Section: In Vivo Assessment Of Or: or Expression In A Blast-induced Rmentioning

confidence: 99%

Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer's Disease

Pasinetti¹

2013

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATEOct PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERIcahn School of Medicine at Mount Sinai 1 Gustave L. Levy Place New York, NY 10029 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTTraumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer's disease (AD). Abnormal tau processing is a common pathological feature of TBI and AD and tau neuropathology plays a key role in both TBI complications and AD dementia. This study is based on our recent findings of aberrant down-regulation of specific olfactory receptors (OR) as biological indices for TBI and down-regulation of OR TBI biomarkers following TBI might contribute to TBI-related tau neuropathology. We propose that down-regulation of select OR TBI biomarkers in the brain may contribute to the elevation of tau neuropathological phenotypes, thereby promoting the development of AD dementia among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans with exposure to TBI. In Year 1, we found that activation of OR4M1 by a low affinity ligand resulted in reduced tau phosphorylation via JNK signaling pathway and a manuscript was published based on this finding. We constructed a virtual 3D structure model for OR4M1 to screen high affinity ligands. Fifty Seven (57) compounds were identified and clustered into 32 clusters based on their structure similarities. We found significant decrease of the blood OR contents in a rat model of TBI. Outcomes from our study will provide a better understanding of TBI complications and how it is related to AD. (Zhao et al., 2013). In addition, we found down-regulation of these ORs is significantly correlated with the severity of brain injury and TBI-specific symptoms, and a two-biomarker panel, comprised of OR11H1 and OR4M1, provides the best criterion for segregating the ...

show abstract

“…MPI is a library specification for message-passing programming, widely used for parallel computing in a single computing cluster system [17] and has been a feature of DOCK since version 5.0 [18]. The node where DOCK MPI is invoked becomes the master node and takes the role of delivering compound-target pairs to be scored by DOCK MPI processes executed on slave nodes within the cluster.…”

Section: Mpi (Message Passing Interface)mentioning

confidence: 99%