A new model for calculating atomic charges in molecules

Gasteiger, Johann; Marsili, Mario

doi:10.1016/s0040-4039(01)94977-9

Cited by 523 publications

(416 citation statements)

References 8 publications

Supporting

Mentioning

394

Contrasting

Unclassified

Order By: Relevance

“…In the first experiment, the ligand was docked using AutoDock with Gasteiger 49 (i.e., default) charges for both the ligand and the receptor. In a second experiment, Gasteiger charges were used for the ligand, and potential-derived charges on the receptor were taken from the AMBER force field.…”

Section: Methodsmentioning

confidence: 99%

Assessing the Role of Polarization in Docking

et al. 2008

View full text Add to dashboard Cite

We describe a strategy for including ligand and protein polarization in docking that is based on the conversion of induced dipoles to induced charges. Induced charges have a distinct advantage in that they are readily implemented into a number of different computer programs, including many docking programs and hybrid QM/MM programs; induced charges are also more readily interpreted. In this study, the ligand was treated quantum mechanically to avoid parametrization issues and was polarized by the target protein, which was treated as a set of point charges. The induced dipole at a given target atom, due to polarization by the ligand and neighboring residues, was reformulated as induced charges at the given atom and its bonded neighbors, and these were allowed to repolarize the ligand in an iterative manner. The final set of polarized charges was evaluated in docking using AutoDock 4.0 on 12 protein-ligand systems against the default empirical Gasteiger charges, and against nonpolarized and partially polarized potential-derived charges. One advantage of AutoDock is that the best rmsd structure can be identified not only from the lowest energy pose but also from the largest cluster of poses. Inclusion of polarization does not always lead to the lowest energy pose having a lower rmsd, because docking is designed by necessity to be rapid rather than accurate. However, whenever an improvement in methodology, corresponding to a more thorough treatment of polarization, resulted in an increased cluster size, then there was also a corresponding decrease in the rmsd. The options for implementing polarization within a purely classical docking framework are discussed.2008112

show abstract

Section: Methodsmentioning

confidence: 99%

Assessing the Role of Polarization in Docking

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The model was initially generated in a reasonable low energy conformation using Concord (45,46), a program widely used to generate three-dimensional structures. This model was then optimized by energy minimization using the Sybyl 6.6 Tripos force field with atomic charges calculated by the method of Gasteiger-Hü ckel (47)(48)(49). The molecular surface was visualized as a Connolly dot surface.…”

Section: Methodsmentioning

confidence: 99%

Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368

Tokita¹,

Hocart²,

Katsuno³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Peptoid antagonists are increasingly being described for G protein-coupled receptors; however, little is known about the molecular basis of their binding. Recently, the peptoid PD168368 was found to be a potent selective neuromedin B receptor (NMBR) antagonist. To investigate the molecular basis for its selectivity for the NMBR over the closely related receptor for gastrin-releasing peptide (GRPR), we used a chimeric receptor approach and a site-directed mutagenesis approach. Mutated receptors were transiently expressed in Balb 3T3. The extracellular domains of the NMBR were not important for the selectivity of PD168368. However, substitution of the 5th upper transmembrane domain (uTM5) of the NMBR by the comparable GRPR domains decreased the affinity 16-fold. When the reverse study was performed by substituting the uTM5 of NMBR into the GRPR, a 9-fold increase in affinity occurred. Each of the 4 amino acids that differed between NMBR and GRPR in the uTM5 region were exchanged, but only the substitution of Phe 220 for Tyr in the NMBR caused a decrease in affinity. When the reverse study was performed to attempt to demonstrate a gain of affinity in the GRPR, the substitution of Tyr 219 for Phe caused an increase in affinity. These results suggest that the hydroxyl group of Tyr 220 in uTM5 of NMBR plays a critical role for high selectivity of PD168368 for NMBR over GRPR. Receptor and ligand modeling suggests that the hydroxyl of the Tyr 220 interacts with nitrophenyl group of PD168368 likely primarily by hydrogen bonding. This result shows the selectivity of the peptoid PD168368, similar to that reported for numerous non-peptide analogues with other G protein-coupled receptors, is primarily dependent on interaction with transmembrane amino acids.

show abstract

“…Diverse kinds of bond weights (w i ) can be used to encode information related to each bond in the molecule. These bond labels are chemically meaningful numbers such as standard bond distances [68, 105 -107] and standard bond dipoles [68, 105 -107], or even mathematical expressions involving atomic weights such as atomic log P [108], surface area contributions of polar atoms [109], atomic molar refractivities [110], atomic hybrid polarizabilities [111], Gasteiger -Marsilli atomic charges [112], atomic electronegativities in Paulings scale [113] and so on. Here we characterized each bond with the following parameter:…”

Section: Chemical Information and Bond-based Molecular Vectormentioning

confidence: 99%

Discovery of Novel Trichomonacidals Using LDA‐Driven QSAR Models and Bond‐Based Bilinear Indices as Molecular Descriptors

et al. 2009

View full text Add to dashboard Cite

Few years ago, the World Health Organization estimated the number of adults with trichomoniasis at 170 million worldwide, more than the combined numbers for gonorrhea, syphilis, and chlamydia. To combat this sexually transmitted disease, Metronidazole (MTZ) has emerged, since 1959, as a powerful drug for the systematic treatment of infected patients. However, increasing resistance to MTZ, adverse effects associated to high-dose MTZ therapies and very expensive conventional technologies related to the development of new trichomonacidals necessitate novel computational methods that shorten the drug discovery pipeline. Therefore, bond-based bilinear indices, new 2-D bond-based TOMOCOMD-CARDD Molecular Descriptors (MDs), and Linear Discriminant Analysis (LDA) are combined to discover novel antitrichomonal agents. Generated models, using non-stochastic and stochastic indices, are able to classify correctly the 90.11% (93.75%) and the 87.92% (87.50%) of chemicals in the training (test) sets, respectively. In addition, they show large Matthews correlation coefficients (C) of 0.80 (0.86) and 0.76 (0.71) for the training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidences the quality of both models. In order to test the models predictive power, 12 compounds, already proved against Trichomonas vaginalis (Tv), are screened in a simulated virtual screening experiment. As a result, they correctly classified 9 out of 12 (75.00%) and 10 out of 12 (83.33%) of the chemicals, respectively, which were the most important criteria to validate the models. Finally, in order to prove the reach of TOMOCOMD-CARDD approach and to discover new trichomonacidals, these classification functions were applied to a set of QSAR Comb. Sci. 28, 2009, No. 1, 9 -26 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 9 * To whom correspondence should be addressed (contact for chem-and bioinformatics methods) ** Contact for biological assays *** Contact for chemical methods Full Paperseight chemicals which, in turn, were synthesized and tested toward in vitro activity against Tv. As a result, experimental observations confirm theoretical predictions to a great extent, since it is gained a correct classification of 87.50% (7/8) of chemicals. Biological tests also show several candidates as antitrichomonals, since almost all the compounds [VAM2-(3 -8)] exhibit pronounced cytocidal activities of 100% at the concentration of 100 mg/mL and at 24 h (48 h) but VAM2 -2: 99.37% (100%), and it is remarkable that these compounds do not show toxic activity in macrophage assays at this concentration. The Quantitative Structure -Activity Relationship (QSAR) models presented here could significantly reduce the number of synthesized and tested compounds as well as could act as virtual shortcuts to new chemical entities with trichomonacidal activity.

show abstract

A new model for calculating atomic charges in molecules

Cited by 523 publications

References 8 publications

Assessing the Role of Polarization in Docking

Assessing the Role of Polarization in Docking

Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368

Discovery of Novel Trichomonacidals Using LDA‐Driven QSAR Models and Bond‐Based Bilinear Indices as Molecular Descriptors

Contact Info

Product

Resources

About