3DGEN: A system for exhaustive 3D molecular design proceeding from molecular topology

Ivanov, Julian M.; Karabunarliev, Stoyan; Mekenyan, Ovanes G.

doi:10.1021/ci00018a001

Cited by 50 publications

(43 citation statements)

References 6 publications

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“…Using the OASIS system [22,23], the dynamic QSAR method combines an exhaustive conformer generation routine [24] with conformer screening algorithms that can be adapted to explore relationships between specific electronic properties and the biological activity under investigation [21]. The conformer generation technique is described by Ivanov et al [24], and the reader is encouraged to consult this reference for a detailed presentation of the approach.…”

Section: Conformer Generationmentioning

confidence: 99%

“…The conformer generation technique is described by Ivanov et al [24], and the reader is encouraged to consult this reference for a detailed presentation of the approach. Briefly, the technique is a combinatorial procedure that initiates from molecular topology and generates all conformers in the context of steric constraints (e.g., distances between nonbonded atoms, ringclosure limits, torsional resolution) and expert rules (e.g., likelihood of intramolecular hydrogen bonds, cis/trans or ϩ/Ϫ isomers).…”

Section: Conformer Generationmentioning

confidence: 99%

“…With strained molecues the possible violation of imposed geometric constraints are corrected with a strain-relief procedure (''pseudo'' molecular mechanics) based on a truncated force field. In summary, the approach used here incorporates the conformational flexibility of saturated cyclic molecular fragments, as opposed to other conformational analysis techniques which explore conformational space formed by rotations around acyclic single bonds only [24]. Finally, the electronic descriptors of interest for a selected set of conformers can be computed either after geometry optimization or by direct single-point (1SCF) calculations of the unoptimized conformations.…”

Section: Conformer Generationmentioning

confidence: 99%

See 2 more Smart Citations

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

Bradbury

Ankley

Mekenyan

1996

Enviro Toxic and Chemistry

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Abstract-A diverse group of xenobiotics has a high binding affinity to the estrogen receptor (ER), suggesting that it can accommodate large variability in ligand structure. Relationships between xenobiotic structure, binding affinity, and estrogenic response have been suggested to be dependent on the conformational structures of the ligands. To explore the influence of conformational flexibility on ER binding affinity, a quantitative structure-activity relationship (QSAR) study was undertaken with estradiol, diethylstilbestrol, and a set of polychlorinated hydroxybiphenyls (PCHBs) of environmental concern. Although the low-energy minima of the PCHB congeners suggested that interconversions among conformers were likely, the electronic parameters associated with the conformer geometries for a specific PCHB congener could vary significantly. The results of the QSAR analysis suggested that among the PCHBs studied, the most polarizable conformers (lower absolute volume polarizability values) were most closely associated with ER binding affinity. Across the set of ''polarizable'' conformers, which did not include the low-energy gas-phase conformers, the electron donating properties of the hydroxy moiety and the aromatic component of the estradiol A ring analogue in the PCHBs were found to be correlated with higher ER binding affinity.

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Section: Conformer Generationmentioning

confidence: 99%

Section: Conformer Generationmentioning

confidence: 99%

Section: Conformer Generationmentioning

confidence: 99%

See 1 more Smart Citation

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

Bradbury

Ankley

Mekenyan

1996

Enviro Toxic and Chemistry

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“…In considering that the most polarizable chlorine atoms in PCBs are those in the lateral positions, a second charge transfer interaction, or cleft binding, between these lateral chlorine atoms and putative electron donor regions that likely constitute the interior pockets in the receptor has been proposed (7,22). Tables 1 and 2 (2,4,8,24 (23,(25)(26)(27) where n is the number of conformers (the number of actual compounds from which the conformers were generated is given in parentheses), r2 is the coefficient of determination, s2 is the variance, F is Fisher's criterion, and r?v2 and s 2 are the corresponding statistics for the "leave one out" cross-validation analysis (36 The negative coefficient between GIW and the positive coefficients with log P and Lmax are consistent with the assumption that the cleft type of binding is influenced by interaction with the lateral (meta-and para-) chlorine atoms (7,9 PCBs in group B. Group B contains tetrachlorobiphenyl with an array of para substituents on the second ring having widely varying polarity and electron acceptor properties.…”

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confidence: 99%

A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics.

Mekenyan

Veith

Call

et al. 1996

Environ Health Perspect

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Because of their widespread occurrence and substantial biological activity, halogenated aromatic hydrocarbons such as polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) comprise one of the more important classes of contaminants in the environment. Some chemicals in this class cause adverse biological effects after binding to an intracellular cytosolic protein called the aryl hydrocarbon receptor (AhR). Toxic responses such as thymic atrophy, weight loss, immunotoxicity, and acute lethality, as well as induction of cytochrome P4501A1, have been correlated with the relative affinity of PCBs, PCDFs, and PCDDs for the AhR. Therefore, an important step in predicting the effects of these chemicals is the estimation of their binding to the receptor. To date, however, the use of quantitative structure activity relationship (QSAR) models to estimate binding affinity across multiple chemical classes has shown only modest success possibly due, in part, to a focus on minimum energy chemical structures as the active molecules. In this study, we evaluated the use of structural conformations other than those of minimum energy for the purpose of developing a model for AhR binding affinity that encompasses more of the halogenated aromatic chemicals known to interact with the receptor. Resultant QSAR models were robust, showing good utility across multiple classes of halogenated aromatic compounds. Images Figure 1. A Figure 1. B Figure 1. C Figure 2. Figure 3. Figure 4. Figure 5.

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“…Each of the generated conformations was submitted to a strain minimization technique (pseudo-molecular mechanics, PMM) that is based on a simple energy-like function, where only the electrostatic terms are omitted [33]. Subsequently, conformational degeneracy, due to molecular symmetry and geometry convergence was detected within a 60 range of torsion angle differences.…”

Section: Genetic Algorithm For Conformational Coveragementioning

confidence: 99%

QSAR Modeling of Antimycobacterial Activity and Activity Against Other Bacteria of 3-Formyl Rifamycin SV Derivatives

Dimov

Nedyalkova

Haladjova

et al. 2001

Quant. Struct.-Act. Relat.

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Rifamycins form a class of antibiotics with a specific potency as drug against tuberculosis via inhibition of the DNA-dependent RNA polymerase. In the present study, literature data on the antibacterial potency against Mycobacterium tuberculosis and other bacteria of 53 derivatives of 3-formyl rifamycin SV are subjected to a QSAR analysis using AM1-based quantum chemical descriptors and the recently introduced dynamic approach that allows explicit consideration of the conformational space of properly generated 3D structures. Data pre-treatment includes normalization of the minimum inhibition concentration (MIC) values of ordinary bacteria using the well-known antituberculosis drug rifampicine as reference compound (RIA), and averaging over the different strains as motivated by a mathematical analysis of the two-step inhibition process. For both this generalized potency against ordinary bacteria and the antimycobacterial activity, QSAR modelling yields 3-variable regression equations with acceptable statistics for screening purposes (r 2 around 0.60), which however differ partly in the stepwise-selected molecular descriptors and the respective conformers. While both types of activity are increased by increasing HOMO energy reflecting an increased electron donor capability and tendency to undergo hydroquinone-semiquinone-quinone oxidation, the models differ in the best 2nd and 3rd local quantum chemical descriptors, pointing to partially conflicting electronic structure requirements for optimal antimycobacterial activity and generalized activity against other bacteria. The discussion includes a detailed mechanistic analysis of the underlying bioreactivity aspects.

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3DGEN: A system for exhaustive 3D molecular design proceeding from molecular topology

Cited by 50 publications

References 6 publications

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics.

QSAR Modeling of Antimycobacterial Activity and Activity Against Other Bacteria of 3-Formyl Rifamycin SV Derivatives

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