Peer-reviewed publications on the use of Molecular Topology


Charge indexes. New topological descriptors
J. Gálvez, R. Garcia-Domenech, M.T. Salabert-Salvador, R. Soler, Charge indicies. New topological descriptors, J. Chem. Inf. Comput. Sci. 34 (1994) 520-525.

New topological descriptors, namely “charge indexes, are presented in this paper. Their ability for the description of the molecular charge distribution is established by correlating them with the dipole movement of a heterogeneous set to hydrocarbons, as well as with the boiling temperature of alkanes and alcohols and the vaporization enthalpy of alkanes. Moreover, it clearly demonstrated that this ability is higher than that shown by the χ connectivity and Weiner indexes.

On a topological interpretation of electronic and vibrational molecular energies
J. Gálvez, On a topological interpretation of electronic andvibrational molecular engergies, J. Mol. Struct. 429 (1998) 255-264.

Prediction of properties of chiral compounds by molecular topology
J.V. de Julián-Ortiz, C. de Gregorio Alapont, I. Ríos-Santamarina, R.Garcia-Domenech, J. Gálvez, Prediction of properties of chiralcompounds by molecular topology, J. Mol. Graphics and Modeling 16(1998) 14-18.

Departamento de Quimica Fisica, Facultad de Farmacia, Universitat de Valencia, Spain.

A common assumption in chemistry is that chiral behavior is associatedwith 3-D geometry. However, chiral information is related to symmetry,which allows the topological handling of chiral atoms by weightedgraphs and the calculation of new descriptors that give a weight to thecorresponding entry in the main diagonal of the topological matrix. Inthis study, it is demonstrated that, operating in this way, chiraltopological indices are obtained that can differentiate thepharmacological activity between pairs of enantiomers. The 50%inhibitory concentration (IC50) values of the D2 dopamine receptor andthe sigma receptor for a group of 3-hydroxy phenyl piperidines arespecifically predicted. Moreover, the sedative character of a group ofchiral barbiturates can be identified.

Articles on the use of Molecular Topology in Drug Discovery & Design


Topological approach to analgesia
J. Gálvez, R. Garcia-Domenech, J.V. de Julián-Ortiz, R. Soler, Topological approach to analgesia, J. Chem. Inf. Comput. Sci. 34 (1994) 1198-1203.

Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Spain.

In this study we show that by making use of the molecular connectivity indicies, including a new index, which we denominate “δt ” and which is obtained from a linear combination of the indicies, as well as from an “ Ε” form index, it is possible to discriminate minor (nonnarcotic) analgesic character with great efficiency, as well as forseeing the analgesic potency of the analyzed compounds, which represents, without a doubt, a powerful tool for the rational design of new analgesic drugs. 

Topological approach to drug design
J. Gálvez, R. Garcia-Domenech, J.V. de Julián-Ortiz, R. Soler, Topological approach to drug design, J. Chem. Inf. Comput. Sci. 35 (1995) 272-284.
 
Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Spain.

In this paper we demonstrated that by an adequate combination of different topological indices it is possible to select and design new active compounds in different therapeutical scopes, with a very high efficiency level. Particularly successful in the search of new "lead drugs", the results show the surprising ability of the topological methods to describe molecular structures. 

New cytostatic agents obtained by molecular topology
J. Gálvez, M.J. Gomez-Lechón, R. Garcia-Domenech, J.V. Castell, New cytostatic agents obtained by molecular topology, Bioorganic & Medicinal Chemistry Letters Vol. 6, No. 19 (1996) 2301-2306. 

Pharmacological distribution diagrams: A tool for de novo drug design
J. Gálvez, R. Garcia-Domenech, J.V. de Julián-Ortiz, L. Popa, Pharmacological distribution diagrams: a tool for de novo drug design, J. Mol. Graphics 14 (1996) 272-276.

Unidad de Investigacion de Diseno de Farmacos y Conectividad Molecular, Facultad de Farmacia, Universidad de Valencia, Burjassot, Spain.

Discriminant analysis applied to SAR studies using topological descriptors allows us to plot frequency distribution diagrams: a function of the number of drugs within an interval of values of discriminant function vs. these values. We make use of these representations, pharmacological distribution diagrams (PDDs), in structurally heterogeneous groups where generally they adopt skewed Gaussian shapes or present several maxima. The maxima afford intervals of discriminant function in which exists a good expectancy to find new active drugs. A set of beta-blockers with contrasted activity has been selected to test the ability of PDDs as a visualizing technique, for the identification of new beta-blocker active compounds.

Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds
J.V. de Julián-Ortiz, J. de Gálvez, C. Muñoz-Collado, R. Garcia-Domenech, C. Gimeno-Cardona, Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds, J. Med. Chem. 42 (1999) 3308-3314.

Unidad de Investigacion de Diseno de Farmacos y Conectividad Molecular, Facultat de Farmacia, and Departamento de Microbiologia, Hospital Clinico Universitario, Universitat de Valencia, Spain. julian@colom.combios.es

The activity of new anti-HSV-1 chemical structures, designed by virtual combinatorial chemical synthesis and selected by a computational screening, is determined by an in vitro assay. A virtual library of phenol esters and anilides was formed from two databases of building blocks: one with carbonyl fragments and the other containing both substituted phenoxy and phenylamino fragments. The library of virtually assembled compounds was computationally screened, and those compounds which were selected by our mathematical model as active ones were finally synthesized and tested. Our antiviral activity model is a "tandem" of four linear functions of topological graph-theoretical descriptors. A given chemical structure was selected as active if it satisfies every discriminant equation in that model. The final result was that five new structures were selected, synthesized, and tested: all of them demonstrated activity, and three showed appreciable anti-HSV-1 activity, with IC(50) values of 0.9 microM. The same model, applied to a database of known compounds, has identified the anti-herpes activity of the following compounds: 3,5-dimethyl-4-nitroisoxazole, nitrofurantoin, 1-(pyrrolidinocarbonylmethyl)piperazine, nebularine, cordycepin, adipic acid, thymidine, alpha-thymidine, inosine, 2, 4-diamino-6-(hydroxymethyl)pteridine, 7-(carboxymethoxy)-4-methylcoumarin, 5-methylcytidine, and others that showed less activity.

Prediction of quinolone activity against mycobacterium avium by molecular topology and virtual computational screening
R. Gozalbes, M. Brun-Pascaud, R. Garcia-Domenech, J. Gálvez, P.M. Girard, J.P. Doucet, F. Derouin, Prediction of quinolone activity against mycobacterium avium by molecular topology and virtual computational screening, Antimicrobial agents and chemotherapy Vol. 44 No. 10 (2000) 2764-2770.

Optimization of a mathematical topological pattern for the prediction of antihistaminic activity
M.J. Duart, R. Garcia-Domenech, G.M. Antón-Fos, J. Gálvez, Optimization of a mathematical topological pattern for the predication of antihistaminic activity, J. Mol. Graphics and Modeling 15 (2001) 561-572.

Predication of the chemiluminescent behavior of pharmaceuticals and pesticides
L. Lahuerta Zamora, Y. Fuster Mestre, M.J. Duart, G.M. Antón Fos, R. Garcia-Domenech, J. Gálvez Álvarez, J. Martínez Calatayud, Prediction of the chemiluminescent behavior of pharmaceuticals and pesticides, Anal. Chem. 73 (2001) 4301-4306.

General topological patterns of known drugs
J. Gálvez, J.V. de Julián-Ortiz, R. Garcia-Domenech, General topological patterns of known drugs, J. Mol. Graphics and Modeling 20 (2001) 84-94.

Search of a topological pattern to evaluate toxicity of heterogeneous compounds
R. Garcia-Domenech, J.V. de Julián-Ortiz, M. J. Duart, J.M. Garcia-Torrecillas, G.M. Anton-Fos, I. Ríos-Santamarina, C. de Gregorio Alapont, J. Gálvez, Search of a topological pattern to evaluate toxicity of heterogeneous compounds, SAR and QSAR in Environmental Research, 2001, Vol. 12, pp. 237-254

New agents active against Myobacterium avium complex selected by molecular topology: a virtual screening method
Angeles Garcia-Garcia, Jorge Galvez, Jesus-Vicente de Julian-Ortiz, R. Garcia-Domenech, Carlos Munoz, Remedios Guna, and Rafael Borras, New agents active against Myobacterium avium complex selected by molecular topology: a virtual screening method, Journal of Antimicrobal Chemotherapy (2004) 53, 65-73
 
New hypoglycaemic agents selected by molecular topology
C. Calabuig, G.M. Anton-Fos, J. Galvez, R. Garcia-Domenach, New hypoglycaemic agents selected by molecular topology, International journal of pharmaceutics 278 (2004) 111-118

Getting new bronchodilator compounds from molecular topology
Rios-Santamarina Inmaculada, Garcia-Domenech Ramon, Galvez Jorge, Morcillo Esteban Jesus, Santamaria Pedro, Cortijo Julio, Getting new bronchodilator compounds from molecular topology, European journal of pharmaceutical science (2004) 1120

Prediction of molecular volume and surface of alkanes by molecular topology
Jorge Galvez, rediction of molecular volume and surface of alkanes by molecular topology, J. Chem. Inf. Comput. Sci. 

Structural invariants for the prediction of relative toxicities of polychlorodibenzo-p-dioxins and dibenzofurans
J.M. Luco, J. Galvez, R. Garcia-Domenech, and J.V. de Julian-Ortiz, Structural invariants for the prediction of relative toxicities of polyshlorodibenzo-p-dioxins and dibenzofurans, Molecular Diversity, 8: 331-342, 2004. 

Computational methods in developing quantitative structure-activity relationships (QSAR): a review.
Dudek AZ, Arodz T, Gálvez J. Comb Chem High Throughput Screen. 2006 Mar;9(3):213-28.

Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship (QSAR) analysis, a field with established methodology and successful history. In this review, we discuss the computational methods for building QSAR models. We start with outlining their usefulness in high-throughput screening and identifying the general scheme of a QSAR model. Following, we focus on the methodologies in constructing three main components of QSAR model, namely the methods for describing the molecular structure of compounds, for selection of informative descriptors and for activity prediction. We present both the well-established methods as well as techniques recently introduced into the QSAR domain. 


Publications Related to Medisyn Compound Discoveries


Novel Ras pathway inhibitor induces apoptosis and growth inhibition of K-ras-mutates cancer cells in vitro and in vivo.
Jasinski P, Zwolak P, Terai K, Dudek AZ. Transl Res. 2008 Nov;152(5):203-12. Epub 2008 Oct 11.
 
MT477 is a novel quinoline with potential activity in Ras-mutated cancers. In this study, MT477 preferentially inhibited the proliferation of K-ras-mutated human pulmonary (A549) and pancreatic (MiaPaCa-2) adenocarcinoma cell lines, compared with a non-Ras-mutated human lung squamous carcinoma cell line (H226) and normal human lung fibroblasts. MT477 treatment induced apoptosis in A549 cells and was associated with caspase-3 activation. MT477 also induced sub-G1 cell-cycle arrest in A549 cells. Although we found that MT477 partially inhibited protein kinase C (PKC), it inhibited Ras directly followed in time by inhibition of 2 Ras downstream molecules, Erk1/2 and Ral. MT477 also caused a reorganization of the actin cytoskeleton and formation of filopodias in A549 cells; this event may lead to decreased migration and invasion of tumor cells. In a xenograft mouse model, A549 tumor growth was inhibited significantly by MT477 at a dose of 1 mg/kg (P < 0.05 vs vehicle control). Taken together, these results support the conclusion that MT477 acts as a direct Ras inhibitor. This quinoline, therefore, could potentially be active in Ras-mutated cancers and could be developed extensively as an anticancer molecule with this in mind.


A novel quinoline, MT477: suppresses cell signaling through Ras molecular pathway, inhibits PKC activity, and demonstrates in vivo anti-tumor activity against human carcinoma cell lines.
Jasinski P, Welsh B, Galvez J, Land D, Zwolak P, Ghandi L, Terai K, Dudek AZ. Invest New Drugs. 2008 Jun;26(3):223-32. Epub 2007 Oct 24.
 
MT477 is a novel thiopyrano[2,3-c]quinoline that has been identified using molecular topology screening as a potential anticancer drug with a high activity against protein kinase C (PKC) isoforms. The objective of the present study was to determine the mechanism of action of MT477 and its activity against human cancer cell lines. MT477 interfered with PKC activity as well as phosphorylation of Ras and ERK1/2 in H226 human lung carcinoma cells. It also induced poly-caspase-dependent apoptosis. MT477 had a dose-dependent (0.006 to 0.2 mM) inhibitory effect on cellular proliferation of H226, MCF-7, U87, LNCaP, A431 and A549 cancer cell lines as determined by in vitro proliferation assays. Two murine xenograft models of human A431 and H226 lung carcinoma were used to evaluate tumor response to intraperitoneal administration of MT477 (33 microg/kg, 100 microg/kg, and 1 mg/kg). Tumor growth was inhibited by 24.5% in A431 and 43.67% in H226 xenografts following MT477 treatment, compared to vehicle controls (p < 0.05). In conclusion, our empirical findings are consistent with molecular modeling of MT477's activity against PKC. We also found, however, that its mechanism of action occurs through suppressing Ras signaling, indicating that its effects on apoptosis and tumor growth in vivo may be mediated by Ras as well as PKC. We propose, therefore, that MT477 warrants further development as an anticancer drug.