Minimal Topological Difference Research Articles

QSAR by Minimal Topological Difference[s]: Post-Modern Perspectives.

In the context of reconsidering the Quantitative Structure-Activity Relationship (QSAR) methods at the economical level, namely the optimization rules of OECD, the present review unfolds the key features of Minimal Sterical, Monte-Carlo and Minimal Topological Difference (MTD) methods, developed for quantitative treatment of the relations between biological activity of organic chemical compounds (drugs, pesticides, and so on) and their structures. The initial Minimal Steric Difference (MSD) is completed by the three-dimensional variant of the MTD method, being the last one referred to here, while the main principles of validating and guiding a viable QSAR method verified by the analytical-automated MTD, thus enlarging the perspectives of understanding the chemical-biological interaction at the level of ligand-receptor sites, cavity, and walls, with a true service to the future adaptive molecular design.

Chemical Structure-Biological Activity Models for Pharmacophores' 3D-Interactions.

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions.

QSAR study and molecular docking on indirubin inhibitors of Glycogen Synthase Kinase-3

Abstract The current study describes the development of in silico models based on a novel alternative of the MTD-PLS methodology (Partial-Least-Squares variant of Minimal Topologic Difference) developed by our group to predict the inhibition of GSK-3β by indirubin derivatives. The new MTD-PLS methodology involves selection rules for the PLS equation coefficients based on physico-chemical considerations aimed at reducing the bias in the output information. These QSAR models have been derived using calculated fragmental descriptors relevant to binding including polarizability, hydrophobicity, hydrogen bond donor, hydrogen bond acceptor, volume and electronic effects. The MTD-PLS methodology afforded moderate but robust statistical characteristics (R2 Y(CUM) = 0.707, Q2(CUM) = 0.664). The MTD-PLS model obtained has been validated in terms of predictive ability by joined internal-external cross-validation applying Golbraikh-Tropsha criteria and Y-randomization test. The information supplied by the MTD-PLS model has been evaluated against Fujita-Ban outcomes that afforded a statistically reliable model (R2=0.923). Furthermore, the results originated from QSAR models were laterally validated with docking insights that suggested the substitution pattern for the design of new indirubins with improved pharmacological potential against GSK-3β. The new restriction rules introduced in this paper are applicable and provide reliable results in accordance with physico-chemical reality.

MTD-comsia modelling of HMG-CoA reductase inhibitors

The 3D quantitative structure-activity relationship for a series of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors based on the pyrrolylethyl-tetrahydropyranone scaffold was examined using the Minimal Topological Difference (MTD) method and comparative molecular similarity index analysis (CoMSIA). The studied compounds were of the tetrahydro-4-hydroxy-6-[2-(1H)-pyrrol-1-yl]ethyl-2H-pyran-2-one type. In clinical practice, HMG-CoA reductase inhibitors are usually referred to by the generic name statins. The analysis performed using the MTD method showed that voluminous substituents produce a significant biological activity ( 2 R2CV=0.677>0.5; SEECV=0.319 ), while the CoMSIA method added useful information regarding the influence of the steric, electrostatic, hydrophobic, hydrogen bond donor, and acceptor properties on biological activity (R2CV=0.60; r2=0.98).

Application of the MTD‐PLS method to heterocyclic dye–cellulose interactions

AbstractThe minimal topologic difference method in a projection in latent structures variant procedure was applied to a series of heterocyclic monoazo dyes of the type: RC6H4N = NY (R = benzothiazole, benzimidazole, N‐containing aromatic pentacycles; Y = γ acid, H acid, chromotropic acid, R acid). A statistically excellent model was obtained: RX2 = 0.625, RY2 = 0.940, Q2 = 0.822. The analysis of this model reveals the nature of dye–fiber interactions, which determine the dye affinity. Hydrophobic character in the R group and H‐bond donor groups in a specific Y substitution position augment the dye affinity for cellulose. An increase of the polar nature of atoms in R depletes the affinity. Also some lateral substituents belonging to the Y coupling components suffer steric hindrance, and their presence is detrimental for the affinity. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007

Design of Anti-HIV Ligands by Means of Minimal Topological Difference (MTD) Method

Molecular modeling and MTD methods are useful tools to assess both qualitative(SAR) and quantitative (QSAR) chemical structure-biological activity relationships. The 1-[(2-hydroxiethoxi)-methyl]-6-(phenylthio)thymine congeners (HEPT ligands) show in vitroanti-viral activity against the type-1 human immunodeficiency virus (HIV-1), which is theetiologic agent of AIDS. This work shows an extensive QSAR study performed upon a largeseries of 79 HEPT ligands using the MTD and HyperChem molecular modeling methods.The studied HEPT ligands are HIV reverse-transcriptase inhibitors. Their geometries wereoptimized and conformational analysis was carried out to build the hypermolecule, whichallowed applying the MTD method. The hypermolecule was used for space mapping of thereceptor’s interaction site. The obtained results show that there are three 3D molecular zonesimportant for the anti-HIV biological activity of the HEPT ligands under study.

MTD—PLS: A PLS Variant of the Minimal Topologic Difference Method. Part 3. Mapping Interactions Between Estradiol Derivatives and the Alpha Estrogenic Receptor.

ChemInformVolume 36, Issue 49 Other Subjects MTD—PLS: A PLS Variant of the Minimal Topologic Difference Method. Part 3. Mapping Interactions Between Estradiol Derivatives and the Alpha Estrogenic Receptor. Ludovic Kurunczi, Ludovic Kurunczi Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorEdward Seclaman, Edward Seclaman Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorTudor I. Oprea, Tudor I. Oprea Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorLuminita Crisan, Luminita Crisan Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorZeno Simon, Zeno Simon Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this author Ludovic Kurunczi, Ludovic Kurunczi Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorEdward Seclaman, Edward Seclaman Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorTudor I. Oprea, Tudor I. Oprea Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorLuminita Crisan, Luminita Crisan Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this authorZeno Simon, Zeno Simon Univ. Med. Pharm. “V. Babes”, RO-300041 Timisoara, Rom.Search for more papers by this author First published: 09 November 2005 https://doi.org/10.1002/chin.200549202AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume36, Issue49December 6, 2005 RelatedInformation

MTD−PLS: A PLS Variant of the Minimal Topologic Difference Method. III. Mapping Interactions between Estradiol Derivatives and the Alpha Estrogenic Receptor

A homogeneous collection of 45 estrogen agonist derivatives with relative binding affinities measured to the estrogen receptor from Ratus norvegicus was used. The quantitative structure-activity relationships were derived using an improved minimal topologic difference (MTD) method in a partial least-squares (PLS) variant. The spatially assigned analysis of fragment properties can provide receptor site maps, within the limits of the existing series. A steric misfit was found for the steroidal position 2; benefic hydrophobic and van der Waals (enhanced by high polarizability) interactions were found for the 17alpha-CH=CH-X group. MTD-PLS mapping results are confirmed by the experimentally derived estradiol-estrogen receptor binding site contacts (based on X-ray crystallography). Our results suggest that this MTD-PLS method can yield useful results for interactions with receptors of unknown 3D structure and, generally, for the steric rigidity of receptor sites.

Theoretical investigations on the role of steroid-skeleton C4 = C5 unsaturation in competitive aromatase inhibition.

A quantitative structure-activity relationship (QSAR) approach by use of the minimal topological difference (MTD) method including 46 derivatives of 4-androstene-3,17-dione and 5 alpha-androstane-3,17-dione is applied to give indications about the role of the C4 = C5 double bond in competitive inhibition of human placental aromatase and about sterical requirements in steroid-aromatase interactions. The inhibitory activity is found to correlate with the sterical MTD variable, hydrophobicity, and pi-system conjugation in the A,B-ring region. A comparison of the MTD results reveals a good agreement with interpretations based on free-energy data derived from inhibition constants. By means of MM2 molecular mechanics and PCILO quantum-chemical calculations, the 4-ene structure is shown to significantly influence conformational features of C19 substituents which are important in enzymatic transformations. While 19-hydroxy-5 alpha-androstane-3,17-dione favour a conformation having the hydroxyl group in the enzyme-directed out-of-ring position, the C4 = C5 double bond energetically enables the steroid to adopt a conformation which can be hydroxylated without internal rotations. According to present theoretical findings, the 4-ene unsaturation thus exerts an indirect conformational influence by hydroxyl positioning appropriate to aromatase interactions and a direct electronic influence by pi conjugation.

MTD Approach to Quantitative Structure-Activity Relationships for Cardiotonic Steroids

A minimal topological difference (MTD) approach is made to describe quantitative structure-activity relationships (QSAR) for the Na+, K+-ATPase inhibitory activity of cardiotonic steroids. The calculations take into account 20 derivatives of digitoxigenin, digoxigenin, and gitoxigenin with small substituents at different sites of the steroid backbone. A multiple correlation coefficient of r = 0.916 is obtained using the MTD and an indicator variable for the presence of a 15 beta substituent. The corresponding receptor map reveals receptor wall vertices in the C11, C12, C15, and C22 regions. Both 3 beta and 16 beta substituents are found to contain receptor cavity vertices. The MTD results are discussed with respect to lactone-ring conformational investigations presented and they are compared with findings of previous structure-activity studies.

QSAR application in chemical carcinogenesis. II. QSAR analysis of a class of carcinogenesis inhibitor: retinoids.

Quantitative structure-activity relationships for the reversion of keratinization of hamster tracheal cell organ culture by structurally related retinoids were formulated. Their biological activities (ED50 . M) were correlated with the following parameters: the minimal topological difference (describing the fit of the considered molecules with a possible receptor site) and the lipophilicity constants. For computation purposes the retinoids were divided in three series (A, B and C) according to structural modifications in the cyclic moiety of the molecule, in the polienic chain and in the terminal functional group, respectively. The computed regression equations suggested the importance of the stereochemical features of cyclic moiety (for series A, eq. 1, n = 19, r = 0.926, F = 48.19) and of the uninterrupted conjugation for the polienic chain (for series B, eq. 6, n = 11, r = 0.954, F = 39.39) for the biological activity. In order to check the prediction potential of the regression equation computed for the overall set of compounds (eq. 10, n = 53, r = 0.853, F = 32.11), it was used to calculate the ED50 for a test series of 15 retinoids. The correlation obtained between ED50 exp and ED50 calc for this series was r = 0.916, F = 60.25. The nature of the receptor site possibly involved in the interaction with retinoids was discussed.

A quantitative structure-activity analysis of the mutagenic and carcinogenic action of 43 structurally related heterocyclic compounds.

Quantitative structure-activity relationships for the carcinogenicity and mutagenicity (against Salmonella typhimurium his- TA98, TA100 and TA1537 strains) of 43 structurally related heterocyclic compounds were formulated. The compounds investigated belong to the following two series of congeners : (a) benzo(thio)-pyranoquinolines and (b) benzo(thio)pyranoindoles. Their biologic activities were correlated with the following parameters : (a) the minimal topological difference (describing the fit of the considered molecules with a possible receptor, enzyme or DNA) and (b) the lipophilicity constants. The computed regression equations suggest that the structural requirements for carcinogenicity are different from those responsible for mutagenicity in the Ames test.