In this review article, we will explore the foundations of different classes of docking and scori... more In this review article, we will explore the foundations of different classes of docking and scoring functions, their possible limitations, and their suitable application domains. We also provide assessments of several scoring functions on weakly-interacting protein-ligand complexes, which will be useful information in computational fragment-based drug design or virtual screening.
Taking account of the presence of water molecules is sometimes crucial for free energy calculatio... more Taking account of the presence of water molecules is sometimes crucial for free energy calculations to predict binding ability of molecules to receptors, a main subject for drug design. This mini-review seeks to identify the importance of knowing the influence of these molecules in such studies to better achieve correct predictions for drug candidates. Participation of some water molecules need to be considered in docking studies although they have been usually neglected.
SUMMARYThe in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic p... more SUMMARYThe in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1–4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1–4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1–3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.
The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and... more The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and DA of two diazatetraester pyrazole crowns containing appended N-(9H-fluoren-9-yl) and N-(naphth-2-ylmethyl) functions, in a water/ethanol 70:30 mixture at physiological pH, are described.
The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 ... more The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.
Page 1. M. F. Braiia, JM Castellano, MJ R. Yunta 641 Synthesis of N,N'-Bis( phenylsulfonyl)-... more Page 1. M. F. Braiia, JM Castellano, MJ R. Yunta 641 Synthesis of N,N'-Bis( phenylsulfonyl)-1,2-bis(4-pyridyl)ethylenediamines Miguel F. Braiia" a, Jose M. Castellano", and Maria JR Yunta Knoll-MADE S. A." Avda. Burgos 91 ...
By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-d... more By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-diethanolamine (R = Me, Bu) and dibutyltin oxide have been reacted with 1H-pyrazole-3,5-dicarbonyl dichloride to afford 26-membered diaza tetraester crowns (1, R = Me; 3, R = Bu) and 39-membered triaza hexaester crowns (2, R = Me; 4, R = Bu). The new structures were identified from their analytical and spectroscopic ((1)H and (13)C NMR, FAB-MS, and/or ESI-MS) data. Both diaza tetraester crowns (1 and 3), containing two 1H-pyrazole units, self-assemble into dimeric species through the formation of four hydrogen bonds involving the two NH pyrazole groups and the two tertiary amine groups of both crowns, as proved by X-ray crystallography and NMR analysis. Preliminary NMR, ESI-MS, MALDI-TOF-MS, and molecular modeling studies suggest that, in CDCl(3) solution, 1 interacts with ethyleneurea (ETU), affording 1:1, 2:1, and 2:2 1-ETU complexes.
Computational techniques are widely used to reduce costs associated with new drug development wit... more Computational techniques are widely used to reduce costs associated with new drug development with the ability to bind a specific molecular target. These studies need a Brookhaven protein data bank structure sample of the enzyme interaction with an inhibitor of adequate size. In this context, a new computational methodology is postulated to be used when there are no published samples fulfilling this requirements. In this study, 7 compounds, which showed anti‐T. cruzi, L. donovani and L. infantum properties, and proved to be inhibitors of their Fe‐SOD enzymes, have been theoretically evaluated against related parasites Fe‐SOD enzymes, which have been proposed as targets for antiparasitic drugs. This methodology may be applied to similar cases and also to generate starting structures to be used with different CADD methods
The affinity and the binding mode of two benzo[g]phthalazine compounds, functionalized with one o... more The affinity and the binding mode of two benzo[g]phthalazine compounds, functionalized with one or two 2-(imidazole-4-yl)-ethylamine groups, to DNA and RNA models have been evaluated by means of UV-Vis, emission...
In this review article, we will explore the foundations of different classes of docking and scori... more In this review article, we will explore the foundations of different classes of docking and scoring functions, their possible limitations, and their suitable application domains. We also provide assessments of several scoring functions on weakly-interacting protein-ligand complexes, which will be useful information in computational fragment-based drug design or virtual screening.
Taking account of the presence of water molecules is sometimes crucial for free energy calculatio... more Taking account of the presence of water molecules is sometimes crucial for free energy calculations to predict binding ability of molecules to receptors, a main subject for drug design. This mini-review seeks to identify the importance of knowing the influence of these molecules in such studies to better achieve correct predictions for drug candidates. Participation of some water molecules need to be considered in docking studies although they have been usually neglected.
SUMMARYThe in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic p... more SUMMARYThe in vitro leishmanicidal activity and cytotoxicity of pyrazole-containing macrocyclic polyamines 1–4 was assayed on Leishmania infantum and Leishmania braziliensis species. Compounds 1–4 were more active and less toxic than glucantime and both infection rates and ultrastructural alterations confirmed that 1 and 2 were highly leishmanicidal and induced extensive parasite cell damage. Modifications in the excretion products of parasites treated with 1–3 were also consistent with substantial cytoplasm alterations. Compound 2 was highlighted as a potent inhibitor of Fe-SOD in both species, whereas its effect on human CuZn-SOD was poor. Molecular modelling suggested that 2 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the enzyme`s antioxidant features.
The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and... more The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and DA of two diazatetraester pyrazole crowns containing appended N-(9H-fluoren-9-yl) and N-(naphth-2-ylmethyl) functions, in a water/ethanol 70:30 mixture at physiological pH, are described.
The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 ... more The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.
Page 1. M. F. Braiia, JM Castellano, MJ R. Yunta 641 Synthesis of N,N'-Bis( phenylsulfonyl)-... more Page 1. M. F. Braiia, JM Castellano, MJ R. Yunta 641 Synthesis of N,N'-Bis( phenylsulfonyl)-1,2-bis(4-pyridyl)ethylenediamines Miguel F. Braiia" a, Jose M. Castellano", and Maria JR Yunta Knoll-MADE S. A." Avda. Burgos 91 ...
By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-d... more By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-diethanolamine (R = Me, Bu) and dibutyltin oxide have been reacted with 1H-pyrazole-3,5-dicarbonyl dichloride to afford 26-membered diaza tetraester crowns (1, R = Me; 3, R = Bu) and 39-membered triaza hexaester crowns (2, R = Me; 4, R = Bu). The new structures were identified from their analytical and spectroscopic ((1)H and (13)C NMR, FAB-MS, and/or ESI-MS) data. Both diaza tetraester crowns (1 and 3), containing two 1H-pyrazole units, self-assemble into dimeric species through the formation of four hydrogen bonds involving the two NH pyrazole groups and the two tertiary amine groups of both crowns, as proved by X-ray crystallography and NMR analysis. Preliminary NMR, ESI-MS, MALDI-TOF-MS, and molecular modeling studies suggest that, in CDCl(3) solution, 1 interacts with ethyleneurea (ETU), affording 1:1, 2:1, and 2:2 1-ETU complexes.
Computational techniques are widely used to reduce costs associated with new drug development wit... more Computational techniques are widely used to reduce costs associated with new drug development with the ability to bind a specific molecular target. These studies need a Brookhaven protein data bank structure sample of the enzyme interaction with an inhibitor of adequate size. In this context, a new computational methodology is postulated to be used when there are no published samples fulfilling this requirements. In this study, 7 compounds, which showed anti‐T. cruzi, L. donovani and L. infantum properties, and proved to be inhibitors of their Fe‐SOD enzymes, have been theoretically evaluated against related parasites Fe‐SOD enzymes, which have been proposed as targets for antiparasitic drugs. This methodology may be applied to similar cases and also to generate starting structures to be used with different CADD methods
The affinity and the binding mode of two benzo[g]phthalazine compounds, functionalized with one o... more The affinity and the binding mode of two benzo[g]phthalazine compounds, functionalized with one or two 2-(imidazole-4-yl)-ethylamine groups, to DNA and RNA models have been evaluated by means of UV-Vis, emission...
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