Building molecular charge distributions from fragments: Application to HIV-1 protease inhibitors

Young, Lynn; Topol, Igor A.; Rashin, A. A.; Burt, Stanley K.

doi:10.1002/(sici)1096-987x(199703)18:4<522::aid-jcc6>3.0.co;2-v

Cited by 7 publications

(4 citation statements)

References 15 publications

(18 reference statements)

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“…Consequently, the κ-agonists were divided into smaller fragments that are suitable for ab initio calculations. The RESP charge-fitting formalism which derives the partial atomic charges of large molecules from the combined ESP of the fragments was employed for 1 − 10 . For instance, U50,488 ( 1 ) was divided into three smaller fragments ( a − d , Chart ) without partitioning the amide bond.…”

Section: Methodsmentioning

confidence: 99%

Conformational Analysis and Automated Receptor Docking of Selective Arylacetamide-Based κ-Opioid Agonists

et al. 1998

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The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.

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Section: Methodsmentioning

confidence: 99%

Conformational Analysis and Automated Receptor Docking of Selective Arylacetamide-Based κ-Opioid Agonists

et al. 1998

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“…The electrostatic properties of the whole molecule are obtained from the sum of contributions of the individual fragments. In the literature, this approach is often called method of reassociation of fragments, and has been used to the determination of atomic partial charges of polypeptides19 and in the determination of partial charges of HIV‐1 protease inhibitors 20…”

Section: Introductionmentioning

confidence: 99%

“…The reassociation method used depends both on the chosen fragmentation scheme and on the method used for the derivation of the electrostatic properties (for methods involving the derivation of atomic partial charges see ref. 20).…”

Section: Introductionmentioning

confidence: 99%

Reassociation of fragments using multicentered multipolar expansions: peptide junction treatments to investigate electrostatic properties of proteins

Dardenne¹,

Werneck²,

Neto³

et al. 2001

J Comput Chem

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ABSTRACT:We report an analysis of three schemes for fragment reassociation using multicentered multipolar expansions derived from ab initio quantum wave functions at the Hartree-Fock/6-31G * LCAO level, two of them involving single-bond partitioning in the peptide bond region, and the third one using a partially overlapping procedure based on a methodology proposed by Vigné-Maeder 21 (OME-overlap of multipolar expansions-reassociation method). The effects of different peptide junction treatments in the derivation of molecular electrostatic potentials and molecular electric fields of three peptide sequences are discussed. The results show that the OME reassociation method gives a better and a more homogeneous description of both the potential and the electric field than the other two treatments. We conclude that the OME method is the most indicated for studies involving electrostatic properties of proteins. Our results also indicate that the use of multicentered multipolar expansions coupled to the OME treatment is the best choice in protein studies including solvent effects using, for example, a continuum boundary method to solve the linearized Poisson-Boltzmann equation.

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“…13, other methods of reassociation of fragments were proposed elsewhere. [24][25][26] D. Target In FR calculations, the charges of first target molecule, C 10 H 22 , were constructed from those of two C 7 H 16 fragment molecules as shown in Figure 1. In other words, the charges of the atoms left to the junction (solid line) of C 10 H 22 ( Figure 1a) were taken from those left to the junction of the left fragment molecule (Figure 1b) while charges of the atoms right to the junction of C 10 H 22 (Figure 1a) were taken from those right to junction of the right fragment molecule ( Figure 1c).…”

Section: Fr Methods To Compute Coulson Mulliken and Natural Chargementioning

confidence: 99%

An Efficient Method to Compute Partial Atomic Charges of Large Molecules Using Reassociation of Fragments

2003

Bulletin of the Korean Chemical Society

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Coulson (ZINDO), Mulliken (MP2/6-31G*) and Natural (MP2/6-31G*) population analyses of several large molecules were performed by the Fragment Reassociation (FR) method. The agreement between the conventional ZINDO (or conventional MP2) and FR-ZINDO (or FR-MP2) charges of these molecules was excellent. The standard deviations of the FR-ZINDO net atomic charges from the conventional ZINDO net atomic charges were 0.0008 for C 10 H 22 (32 atoms), 0.0012 for NH 2-C 16 O 2 H 28-COOH (53 atoms), 0.0014 for NH 3 +-C 16 O 2 H 28-COOH (54 atoms), 0.0017 for NH 2-C 16 O 2 H 28-COO − (52 atoms), 0.0019 for NH 3 +-C 16 O 2 H 28-COO − (53 atoms), 0.0024 for a conjugated model (O=CH-(CH=CH) 15-C=O-(CH=CH) 12-CH=CH 2), 118 atoms), 0.0038 for aglycoristocetin (C 60 N 7 O 19 H 52 + , 138 atoms), 0.0023 for a polypropylene model complexed with a zirconocene catalyst (C 68 H 121 Zr + , 190 atoms) and 0.0013 for magainin (C 112 N 29 O 28 SH 177 , 347 atoms), respectively. The standard deviations of the FR-MP2 Mulliken (or Natural) partial atomic charges from the conventional ones were 0.0016 (or 0.0016) for C 10 H 22 , 0.0019 (or 0.0018) for NH 2-C 16 O 2 H 28-COOH and 0.0033 (or 0.0023) for NH 3 +-C 16 O 2 H 28-COO − , respectively. These errors were attributed to the shape of molecules, the choice of fragments and the degree of ionic characters of molecules as well as the choice of methods. The CPU time of aglycoristocetin, conjugated model, polypropylene model complexed with zirconocene and magainin computed by the FR-ZINDO method was respectively 2, 4, 6 and 21 times faster than that by the normal ZINDO method. The CPU time of NH 2-C 16 O 2 H 28-COOH and NH 3 +-C 16 O 2 H 28-COO − computed by the FR-MP2 method was, respectively, 6 and 20 times faster than that by the normal MP2 method. The largest molecule calculated by the FR-ZINDO method was B-DNA (766 atoms). These results will enable us to compute atomic charges of huge molecules near future.

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Building molecular charge distributions from fragments: Application to HIV-1 protease inhibitors

Cited by 7 publications

References 15 publications

Conformational Analysis and Automated Receptor Docking of Selective Arylacetamide-Based κ-Opioid Agonists

Conformational Analysis and Automated Receptor Docking of Selective Arylacetamide-Based κ-Opioid Agonists

Reassociation of fragments using multicentered multipolar expansions: peptide junction treatments to investigate electrostatic properties of proteins

An Efficient Method to Compute Partial Atomic Charges of Large Molecules Using Reassociation of Fragments

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