Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

Leach, Andrew R.; Prout, Keith; Dolata, Daniel P.

doi:10.1007/bf00125015

Cited by 23 publications

(4 citation statements)

References 5 publications

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“…We have found torsion constraints particularly helpful in docking larger, highly flexible ligands. This requires knowledge of the conformational characteristics of the ligand, which may be inferred from experimental evidence or, if unavailable, a variety of exhaustive and/or artificialintelligence-based [30] conformational search procedures, such as COBRA*.…”

Section: Discussionmentioning

confidence: 99%

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

Morris

Goodsell

Huey

et al. 1996

J Computer-Aided Mol Des

986

659

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AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.

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Section: Discussionmentioning

confidence: 99%

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

Morris

Goodsell

Huey

et al. 1996

J Computer-Aided Mol Des

986

659

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“…To a suspension of the potassium salt 15 (1.08 g, 4.61 mmol) in ethanol (15 mL) was added 1-(3-chloropropyl)-4-(2-chlorophenyl)piperazine (33) (1.26 g, 4.63 mmol), and the mixture was stirred at reflux for 6 h. After cooling, the solid was collected by filtration, washed with ethanol and water, and recrystallized (Table 1).…”

Section: -[[3-[4-(2-chlorophenyl)-1-piperazinyl]propyl]thio]-56-dimet...mentioning

confidence: 99%

“…Theoretical studies were run on a Silicon Graphics Indigo R3000 workstation. The energetically favorable conformation of the lead compound (molecule 70) was sought using Cobra (Oxford Molecular Ltd., Oxford, U.K.), a software package based on the Wizard system, 33 which processes from the input of a two-dimensional representation of the molecule (in which atom types, connectivity and stereochemistry are defined) and generates acceptable conformations, which were classified according to their potential energy. All of the other molecules used in the study were built using the preferred conformation of molecule 70 as scaffold.…”

Section: -Amino-2[[3[4(2-methoxyphenyl)-1-piperazinyl]propylmentioning

confidence: 99%

[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone Derivatives as High-Affinity, Selective 5-HT_1A Receptor Ligands

et al. 1997

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A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the alpha 1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT1A was 6.8 nM. These results, compared to those for compounds 46 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT1A receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.

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“…computational conformational analysis, to search conformational space and locate conformations at or near energy minima [1][2][3][4][5][6]. Our objectives were to develop a means of rapidly and automatically exploring conformational space for a wide variety of molecules.…”

Section: Introductionmentioning

confidence: 99%

Constitutional, configurational and conformational analysis of transition metal coordination complexes

Leach

1993

J Computer-Aided Mol Des

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A computational approach to conformational analysis is applied to the study of transition metal coordination complexes. The method provides a means of rapidly exploring conformational space without any inherent reliance on energy calculations and is therefore applicable to a wide variety of systems. It has been incorporated into an algorithm which explores the constitutional, configurational and conformational degrees of freedom for a metal ion and a number of potential ligands. The program determines which of the possible coordination complex products could form stable conformations and can therefore be used to rationalise the products obtained from the mixture. The method is illustrated using two cases: the cobalt(III)-triethylenetetramine-glycine system and complexes of diindolopyridine derivatives.

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Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

Cited by 23 publications

References 5 publications

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone Derivatives as High-Affinity, Selective 5-HT_1A Receptor Ligands

Constitutional, configurational and conformational analysis of transition metal coordination complexes

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Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

Cited by 23 publications

References 5 publications

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4

[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone Derivatives as High-Affinity, Selective 5-HT1A Receptor Ligands

Constitutional, configurational and conformational analysis of transition metal coordination complexes

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[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone Derivatives as High-Affinity, Selective 5-HT_1A Receptor Ligands