1,721,323 research outputs found
Tautomeric equilibria of benzopyranoimidazoles: useful insights from quantum chemical calculation and NMR
No full textThe development of novel syntetic strategies for achieving compounds containing the coumarin nucleus condensed to several heterocycles has been the subject of our research for the latter few years. [1] Such heterocycles are pharmacologically relevant as CNS depressants, [2] growth inhibitors of mammalian cancer [3] and also phosphodiesterase VII inhibitors for treatment of immunity-associated diseases. [4]
Recently we reported the synthesis of some substituted benzopyranoimidazolones, and we pointed out the possibility of such heterocycles to exist in solution in at least two tautomeric forms, the N3-H and the N1-H tautomers (Fig. 1). [5] The study and quantitative evaluation of prototropic tautomerism in heterocyclic compounds is of primary interest, influencing both reactivity and biological behavior, for example the ability of a drug to bind the active site of a target enzyme [6]. Unfortunately literature does not report any reliable structural information and neither experimental data concerning tautomerism on pyranoimidazolone nucleus. Furthermore RT NMR experiments conducted by us so far were able to evidence the presence of at least two tautomers only for compound 4d and the attempts previously reported by us to unequivocally assign the preferred tautomeric structure by NMR were unsuccessful. The only result was obtained by N-methylation of compound 4d, were just the N3-CH3 product was isolated both at high and low reaction temperatures. However the reaction condition adopted could have influenced the tautomeric equilibrium. On the other hand tautomerism has been successfully described on various substituted imidazoles by ab-initio and DFT calculations in both gas-phase and solution within the continuum solvent model or evaluating explicit solvent interactions. [7]
In our previous work, where the main object was the development of a synthetic strategy for benzopiranoimidazoles, preliminary quantum chemical calculations explained only in part the tautomeric behavior observed, thus the need of a throughout theoretical and experimental investigation. The relative stability of all the possible tautomers for [1]benzopyrano[3,4-d]imidazol-4(3H)-ones, namely the N3-H (alpha tautomer), N1-H (beta tautomer), coumarin O-H (gamma tautomer) and C2-H (delta tautomer), has been evaluated by mean of HF and B3LYP calculations, including the solvent contribution by the SCRF PCM model. Furthermore the 13C and 1H chemical shifts were calculated by GIAO technique at the HF/6-311+G(2d,p) and B3LYP/TZVP levels of theory both in gas phase and in solution by using the PCM model for DMSO. The calculation of 13C chemical shifts by GIAO technique and the comparison with the experimental has been reported as one of the most reliable methods for the investigation of tautomeric equilibria in solution [8]. Finally, 1H NMR spectra were recorded in CD3COCD3 at 500 Mhz at variable temperature in a range from RT to –60°C in order to evidence the presence of the most probable tautomers by progressively lowering their interconversion rates.
The combination of the above mentioned theoretical techniques and experimental NMR allowed us to demonstrate that:
1.The only relevant tautomeric equilibrium for benzopyranoimidazolones is between alpha and beta forms.
2.All compounds 4a-e are able to exhibit tautomeric equilibrium in polar solvents.
3.The interconversion rate between alpha and beta tautomers is fast, thus by NMR is possibile to detect the presence of both tautomers only at low temperatures, otherwise averaged signals are recorded.
Bibliography
1.[a] E.M. Beccalli, A. Contini and P. Trimarco, Eur. J. Org. Chem., 2003, 3976-3984, [b] E.M. Beccalli, A. Contini and P. Trimarco, Tetrahedron Letters, 2004, 45, 3447-3449.
2.V. L. Savel’ev, N. T. Pryanishnikova, V. A. Zagorevskii, I. V. Chernyakova, O.S. Artamonova, V. V. Shavyrina, L. I. Malysheva, Khim. Farm. Zh. 1983, 17, 697-700; see Chem. Abstr. 1983, 99, 158325.
3.M. Trkovnik, V. Kalaj, D. Kitan, Org. Prep. Proced. Int., 1987, 19, 450-455
4.M. Eggenweiler, J. Rochus, M. Wolf, M. Gassen, O. Poeschke, Merck Patent Gmbh, Germany, PCT Int. Appl. 2001; see Chem. Abstr. 2001, 134, 331619.
5.See ref 1a
6.P. Pospisil, P. Ballmer, G. Folkers, L. Scapozza, Tautomerism of nucleobase derivatives and their score in virtual screening to thymidine kinase, Abstracts of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002
7.[a] O. V. Shishkin, O. S. Sukhanov, L. Gorb and J. Leszczynski, PCCP, 2002, 4, 5359-5364. [b] G. -S. Li, M. F. Ruiz-Lopez, M. S. Zhang, B. Maigret, J. Mol. Struct. (Theochem), 1998, 422, 197-204. [c] E. D. Raczyńska, Anal. Chim. Acta, 1997, 348, 431-441. [d] G. A. Worth, P. M. King, W. G. Richards, Biochem. Biophys. Acta, 1989, 993, 134-136. [e] G. -S. Li, M. F. Ruiz-Lopez, M. -S. Zhang, B. Maigret, J. Phys. Chem., 1997, 101, 7885-7892. [f] F. J. Luque, J. M. Lopez-Bes, J. Cemeli, M. Aroztegui, M. Orozco, Theor. Chem. Acc., 1997, 96, 105-113.
8.[a] N. E. Campillo, C. Montero, J. A. Páez, J. Mol. Struct. (Theochem), 2004, 678, 83-89. [b] E. Kleinpeter and A. Koch, J. Phys. Org. Chem., 2001, 14, 566-576
Disegno, sintesi e valutazione farmacologica di nuovi inibitori della proteina Rac1
No full textUna nuova classe di composti efficaci come inibitori dell’interazione RAC1- TIAM è stata progettata e sintetizzata a partire da reagenti semplici ed economici come nitroacetati, tioli, ortoformiato e ciclopentadiene.[1] I composti sintetizzati differiscono per la stereochimica dei sostituenti installati su uno scaffold norbornanico comune. La preparazione dei composti AR129, 148, 177, 180, 194, 201 si basa su un comune schema sintetico che prevede tre step fondamentali: i) costruzione dello scaffold norbornenico mediante reazione di cicloaddizione di Diels-Alder tra l’opportuno acrilato e ciclopentadiene;[2] ii)funzionalizzazione del doppio legame norbornenico mediante idroarilazione di Heck; iii) amminazione di Buchwald seguita da manipolazioni finali di tipo riduttivo e deprotettivo. La procedura è stata ottimizzata ed è stato operato uno scale-up dei composti AR129 e AR 148. Per quanto riguarda la reazione di idroarilazione di Heck è stata osservata una differente reattività dei nuclei norbornenici ottenuti dalla cicloaddizione che ci ha indotto ad approfondire i fattori che regolano regiochimica e reattività di tale reazione su substrate scope più ampio mettendo in evidenza effetti long-range di EWG in posizione endo con l'orbitale p del doppio legame.[3] Successivi sviluppi hanno dimostrato che la reazione procede con successo anche in assenza di leganti di tipo fosfinico. Inoltre la modellazione della reazione sul norbornene semplice ha messo in luce la possibilità di condurre tale reazione anche in solventi non coordinanti rendendo ipotizzabili meccanismi di reazione alternativi.
Riferimenti:
1. N. Ferri, A. Corsini, P. Bottini, F. Clerici, A. Contini, J Med. Chem., 2009, 52(14), 4087 – 90.
2. A. Ruffoni, A. Contini, S. Pellegrino, M. L. Gelmi, R. Soave, F. Clerici, Tetrahedron., 2012, 68, 1951 – 62.
3. A. Ruffoni, A. Casoni, S. Pellegrino, M. L. Gelmi, F. Clerici, Current Organic Chem. 2012, 16, 2
Consensus Strategies for Challenging Dockings
No full textThe attention toward protein-protein interactions as potential targets for the design of very specific drugs dramatically increased during the last few years. The binding regions involved in protein-protein interactions are rarely deep and well-defined cavities, as found in the active site of an enzyme, but are often characterized by solvent-exposed clefts on the protein surface. This feature makes the definition of a reliable docking protocol quite challenging.
This workshop will be focused upon the development of a docking protocol for the identification of small organic molecules potentially able to interfere with the interaction of two target proteins (hereafter referred as proteins A and B). The study will cover two possible scenarios:
1) The crystal structure of the AB complex is available;
2) The structure of either A or B is available co-crystallized with a known inhibitor.
In both scenarios we will analyze the complex, finding and fixing all possible sources of error and preparing the model for docking experiments (fixing missing residues, assigning the correct protonation state, relaxing the structure through short molecular dynamic runs followed by geometry minimizations). A docking protocol will then be realized and tested through the docking of small databases of compounds with known activity. The results of both scenarios will be compared and discussed.
As consensus between different computational methods might be a key to improve the success rate of a virtual screening procedure, an alternative docking protocol will be also realized by using a different method and software. The two protocols will be tested within a virtual screening case study and those hits identified by each single protocol will be compared to those identified by both protocols applied on a consensus basis
Profili di donne nell’Archivio Contemporaneo del Gabinetto Vieusseux
No full texta cura di A. Contini e A. Scattign
Computational Organic Chemistry: Examples of Applications.
No full textThe interest of the organic chemists toward computational quantum mechanics (QM) is notably grown due to both the increasing performance of modern CPUs and the software optimization for
parallel applications. Indeed, quantum chemistry allows the prediction of several molecular properties (i.e. energy, favored geometry, spectroscopic properties) as well as the investigation
of reaction mechanisms trough an accurate analysis of transition states (TS). In this manuscript we report two examples where quantum-chemical computational techniques were successfully applied
to solve some questions raised within research projects in the field of organic chemistry. The first example concern the study of the tautomerism (a phenomenon of dynamic chemical equilibrium)
of some imidazole derivatives, where their experimentally derived spectroscopic properties were compared with those theoretically computed for the single tautomers. In the second case, computational
QM allowed the rationalization of the "double" reactivity of o-thioquinones toward Diels-Alder cycloadditions. The studies herein reported were performed thanks to the collaboration between the
Università degli Studi di Milano and CILEA, which provided computational facilities
A many-body term improves the accuracy of effective potentials based on protein coevolutionary data
Full text linkThe study of correlated mutations in alignments of homologous proteins proved to be successful not only in the prediction of their native conformation but also in the development of a two-body effective potential between pairs of amino acids. In the present work, we extend the effective potential, introducing a many-body term based on the same theoretical framework, making use of a principle of maximum entropy. The extended potential performs better than the two-body one in predicting the energetic effect of 308 mutations in 14 proteins (including membrane proteins). The average value of the parameters of the many-body term correlates with the degree of hydrophobicity of the corresponding residues, suggesting that this term partly reflects the effect of the solvent
Improving the reliability of MM-PBSA and MM-GBSA binding energy predictions by explicitly considering ligand solvation shells
No full textMolecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) are interesting techniques for drug design/discovery applications, but sometimes the correlation between predicted and experimental binding energies might result unsatisfactory.
Nowadays, a certain effort is focused on ameliorating the solvation term in MM-PB/GBSA calculations and some strategies were applied to obtain a better correlation between calculations and experiments.
Some authors reported that the predictivity of MM-PB/GBSA calculations might be improved by modulating the internal dielectric constant (εin).1 Unfortunately, a universal εin, suitable for all systems was not found and a thorough analysis of the binding pocket is needed to choose the proper value of εin.
MM-PB/GBSA binding energy predictions might also be improved by explicitly considering selected water molecules in the calculation, however this strategy is controversial.2-5
Herein, we report on how the explicit inclusion of variably populated ligand hydration shells might improve the correlation between MM-PB/GBSA computed binding energy and experimental activities.
DNA-topoisomerase, α-thrombin, penicillopepsin, avidin, and neuraminidase complexes with different ligands were considered as test sets, and ligand hydration shells populated by an increasing number of water molecules were systematically evaluated.
We found that the consideration of a hydration shell populated by a number of water residues (Nwat) between 30 and 70 provided in all the considered examples a positive effect on correlation between MM-PB/GBSA calculated binding affinities and experimental activities, with a negligible increment of computational cost.6
REFERENCES
1. Hou, T.; Wang, J.; Li, Y.; Wang, W., J. Chem. Inf. Model. 2011, 51, 69-82.
2. Wong, S.; Amaro, R. E.; McCammon, J. A., J. Chem. Theory Comput. 2009, 5, 422-429.
3. Hayes, J. M.; Skamnaki, V. T.; Archontis, G.; Lamprakis, C.; Sarrou, J.; Bischler, N.; Skaltsounis, A.-L.; Zographos, S. E.; Oikonomakos, N. G., Proteins 2011, 79, 703-19.
4. Freedman, H.; Huynh, L. P.; Le, L.; Cheatham, I. I. I. T. E.; Tuszynski, J. A.; Truong, T. N., J. Phys. Chem. B 2010, 114, 2227-2237.
5. Checa, A.; Ortiz, A. R.; de Pascual-Teresa, B.; Gago, F., J. Med. Chem. 1997, 40 (25), 4136-45.
6. Maffucci, I.; Contini, A., J. Chem. Theory Comput. 2013, 9 (6), 2706-2717
Combining 3D-RISM calculation with hydropathic character for water selection: an application in docking with flexible explicit water
Full text linkDocking and virtual screening with explicit water has become a hot topic within the docking community in the past decade. It was suggested that the bridging water molecules, existed between the ligand and the receptor, are important contributors to binding free energy. Multiple methods are since developed, either through direct evaluation or scoring of crystal waters, or predictions for water positions when crystal waters are in absence. However, the likelihood of introducing human bias increases during the process of water selection. Moreover, wrong choices about water molecules will result in fault screening, giving ineffective candidates. Therefore, in our work, we have combined a well-established water-predicting method, 3D-RISM, and a relatively simple and efficient water selection criteria by evaluating hydropathic characteristic of water molecules. This flow of work has allowed automatic selection of water molecules between protein-ligand or protein-protein interface. We have observed optimistic results in predicting crystal water positions within the binding pocket using several benchmark systems. We will further combine these steps with flexible water docking, included in the PLANTS docking package, to improve virtual screening with explicit waters both in efficiency and accuracy
A semiautomated Nwat-MM-GBSA workflow for fast and accurate predictions of relative binding free energies
No full textDespite the development of high-throughput computational methods able to screen very large libraries in a short time, the reliable prediction of binding free energy can still be important in drug design.1,2 Although quite computationally expensive, molecular dynamics (MD), providing a statistically meaningful conformational ensemble for thermodynamic calculations, are within the most accurate tecqniques to predict interaction free energies of biomolecules. Among MD-based methods, one of the most popular is Molecular Mechanics Poisson−Boltzmann/Generalized Born Surface Area (MM-PB/GBSA).3
We recently reported on how the inclusion of a certain number of explicit waters (Nwat), chosen to be the closest to the ligand atoms, can improve the correlation between MM-PB and GBSA computed binding energy and experimental activities (Fig. 1).4
Fig. : Effect of the inclusion of explicit waters in the correlation of computed and experimental activities for a set of topoisomerase inhibitors
Here, we will present a semiautomated workflow to compute MM-GBSA relative binding energies starting from a set of complexes, either obtained through X-ray crystallography, homology modelling or docking simulations, by taking advantage of GPU calculations and with a minimal effort by the user.
We will also discuss specific examples of application on protein-ligand and protein-protein complexes.
REFERENCES
1. Durrant, J.D.; McCammon, J.A. Molecular dynamics simulations and drug discovery. BMC Biology 2011, 9:71
2. Zhao, H.; Caflish, A. Molecular dynamics in drug design. Eur. J. Med. Chem. 2014, doi:10.1016/j.ejmech.2014.08.004
3. Massova, I.; Kollman, P. Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspect. Drug Discov. 2000, 18 (1), 113-135
4. Maffucci, I.; Contini, A. Explicit Ligand Hydration Shells Improve the Correlation between
MM-PB/GBSA Binding Energies and Experimental Activities J. Chem. Theory Comput. 2013, 9, 2706-2717
Combining 3D-RISM with hydrophatic characteristic water evaluation: first step preparation for further PLANTS virtual screening with flexible explicit water molecules
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