Njogu M. Kimani, J. Matasyoh, M. Kaiser, M. Nogueira, G. Trossini, T. Schmidt
In continuation of a previous quantitative structure-activity relationship (QSAR) study on the antitrypanosomal activity of 69 sesquiterpene lactones (STLs) towards Trypanosoma brucei rhodesiense (Tbr) [1], the causative agent of East African form of human African trypanosomiasis, a QSAR model for a much larger and more diverse set of almost twice as many (130) of such natural products was established in this study. The extended data set has been obtained through a variety of STLs isolated and tested for antitrypanosomal activity within our group and further enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses using various complementary approaches: (1) “Classical” descriptor-based QSAR using a genetic algorithm to select the most relevant variables, i.e. the same approach as in our previous study [1], (2) indicator variables deduced from pharmacophore features obtained from a 3D alignment of the most active molecules as applied in [2] and (3) hologram QSAR (HQSAR) based on molecular fingerprints of fragments extracted from the 2D molecular structure as used, e.g., in [3], have yielded models with good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of conjugated carbonyl groups within the molecular structure, but influenced by their hydrophilic/hydrophobic property and molecular shape References Schmidt, T. J. et al. Antimicrob. Agents Chemother. 2014, 58 (1), 325–332. Schomburg, C. et al. Eur. J. Med. Chem. 2013, 63, 313–320. Trossini, G. H. G. et al. Molecules 2014, 19 (7), 10546–10562.
{"title":"An extended study on quantitative structure-antitrypanosomal activity relationships of sesquiterpene lactones","authors":"Njogu M. Kimani, J. Matasyoh, M. Kaiser, M. Nogueira, G. Trossini, T. Schmidt","doi":"10.3390/ECMC-4-05591","DOIUrl":"https://doi.org/10.3390/ECMC-4-05591","url":null,"abstract":"In continuation of a previous quantitative structure-activity relationship (QSAR) study on the antitrypanosomal activity of 69 sesquiterpene lactones (STLs) towards Trypanosoma brucei rhodesiense (Tbr) [1], the causative agent of East African form of human African trypanosomiasis, a QSAR model for a much larger and more diverse set of almost twice as many (130) of such natural products was established in this study. The extended data set has been obtained through a variety of STLs isolated and tested for antitrypanosomal activity within our group and further enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses using various complementary approaches: (1) “Classical” descriptor-based QSAR using a genetic algorithm to select the most relevant variables, i.e. the same approach as in our previous study [1], (2) indicator variables deduced from pharmacophore features obtained from a 3D alignment of the most active molecules as applied in [2] and (3) hologram QSAR (HQSAR) based on molecular fingerprints of fragments extracted from the 2D molecular structure as used, e.g., in [3], have yielded models with good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of conjugated carbonyl groups within the molecular structure, but influenced by their hydrophilic/hydrophobic property and molecular shape\u0000References\u0000\u0000Schmidt, T. J. et al. Antimicrob. Agents Chemother. 2014, 58 (1), 325–332.\u0000Schomburg, C. et al. Eur. J. Med. Chem. 2013, 63, 313–320.\u0000Trossini, G. H. G. et al. Molecules 2014, 19 (7), 10546–10562.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89073599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including alpha-ketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure–activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series.
{"title":"Discovery of novel endocannabinoid level modulators by modification of old analgesic drugs","authors":"A. Deplano, Monica Demurtas, V. Onnis","doi":"10.3390/ECMC-4-05590","DOIUrl":"https://doi.org/10.3390/ECMC-4-05590","url":null,"abstract":"Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including alpha-ketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure–activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74813251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pramodkumar P. Gupta, V. Kale, V. Bastikar, S. Chhajed, M. Valius, J. Cicenas
Protein EVI2A (Ecotropic viral integration site 2A) is a type 1 single pass membrane protein containing 236 amino acid residues. EVI2A is associated with several human diseases such as schizophrenia and numerous malignancies including breast and ovarian cancers. Protein 3D structure helps in understanding the molecular function of the proteins and their important role in the biological scenario if any. Till date no 3D structure of protein EVI2A has been reported in public or private databases. To fill that gap, we evaluated some computational models including comparative methods, de novo approach, ab initio and threading based methods. The multiple models, including 3D model from I-Tasser, afforded a good agreement of output and structural features. A complete model of protein EVI2A was validated by ProSa and Ramachandran analyses. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package and active site prediction was carried out using CASTp. The predicted model could be a starting point for structural biologists, drug discovery groups, and scientific community to further enhance their studies. .
EVI2A蛋白(Ecotropic viral integration site 2A)是一种含有236个氨基酸残基的1型单通膜蛋白。EVI2A与精神分裂症等几种人类疾病以及包括乳腺癌和卵巢癌在内的许多恶性肿瘤有关。蛋白质三维结构有助于理解蛋白质的分子功能及其在生物场景中的重要作用。迄今为止，在公共或私人数据库中尚未报道蛋白质EVI2A的三维结构。为了填补这一空白，我们评估了一些计算模型，包括比较方法、从头开始方法、从头开始方法和基于线程的方法。多个模型，包括来自I-Tasser的3D模型，提供了很好的输出和结构特征的一致性。通过ProSa和Ramachandran分析验证了完整的EVI2A蛋白模型。使用GROMACS软件包进行分子动力学(MD)模拟和分析，使用CASTp进行活性位点预测。该预测模型可以作为结构生物学家、药物开发小组和科学界进一步加强研究的起点。
{"title":"3D Structure modeling & analysis of transmembrane protein EVI2A from Homo sapiens","authors":"Pramodkumar P. Gupta, V. Kale, V. Bastikar, S. Chhajed, M. Valius, J. Cicenas","doi":"10.3390/ecmc-4-05593","DOIUrl":"https://doi.org/10.3390/ecmc-4-05593","url":null,"abstract":"Protein EVI2A (Ecotropic viral integration site 2A) is a type 1 single pass membrane protein containing 236 amino acid residues. EVI2A is associated with several human diseases such as schizophrenia and numerous malignancies including breast and ovarian cancers.\u0000Protein 3D structure helps in understanding the molecular function of the proteins and their important role in the biological scenario if any. Till date no 3D structure of protein EVI2A has been reported in public or private databases. To fill that gap, we evaluated some computational models including comparative methods, de novo approach, ab initio and threading based methods. The multiple models, including 3D model from I-Tasser, afforded a good agreement of output and structural features. A complete model of protein EVI2A was validated by ProSa and Ramachandran analyses. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package and active site prediction was carried out using CASTp. The predicted model could be a starting point for structural biologists, drug discovery groups, and scientific community to further enhance their studies.\u0000.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86937805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"In silico studies of aminated thioxanthones: bacterial multidrug efflux pumps vs P-glycoprotein","authors":"E. Sousa, Fernando Durães, A. Palmeira, M. Pinto","doi":"10.3390/ECMC-4-05598","DOIUrl":"https://doi.org/10.3390/ECMC-4-05598","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90572262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Enisa Selimović, A. Komolkin, A. Egorov, T. Soldatović
Over the past decades, transition metal complexes have attracted considerable attention in medicinal inorganic chemistry, especially as synthetic metallonucleases and metal-based anticancer drugs that are able to bind to DNA under physiological conditions (Pessoa, J.C., et al. J. Inorg. Biochem. 2011, 105, 637-644). Copper(II) complexes offer various potential advantages as antimicrobial, antiviral, anti-inflammatory, antitumor agents, enzyme inhibitors, chemical nucleases, and they are also beneficial against several diseases like copper rheumatoid and gastric ulcers (Fricker, S.P., Dalton Trans. 2007, 43, 4903-4917). Substitution reactions of square-planar [CuCl2(en)] and square-pyramidal [CuCl2(terpy)] complexes (where en= 1,2-diaminoethane and terpy= 2,2’:6’,2’’- terpyridine) with bio-relevant nucleophiles have been investigated at pH 7.4 in the presence of 0.010 M NaCl. Mechanism of substitution was probed via mole-ratio, kinetic, mass spectroscopy and EPR studies. In the presence of an excess of chloride, the octahedral complex anion [CuCl4(en)]2- forms rapidly while equilibrium reaction was observed for [CuCl2(terpy)]. Different order of reactivity of selected bio-molecules toward Cu(II) complexes was observed. The nature of the buffer just affects the Cu(II) complexes conformational dynamics. According to EPR data L-Methionine forms a most stable complex with [CuCl2(en)] among the bio-ligands considered while [CuCl2(terpy)] complex is very stable and there are no significant changes in its square-pyramidal geometry in the presence of buffers or bio-ligands. The obtained results represent progress in investigation of the mechanism of substitution reactions between Cu(II) complexes and biological relevant nuclepohiles. Also, they provide very useful information for the future design of potential copper-based anticancer drugs (Selimovic, E., et al. J. Coord. Chem. 2018, 71(7), 1003-1019).
在过去的几十年里，过渡金属配合物在药物无机化学中引起了相当大的关注，特别是作为在生理条件下能够与DNA结合的合成金属核酸酶和金属基抗癌药物(Pessoa, J.C等)。j . Inorg。生物化学，2011,5,637-644)。铜(II)配合物在抗菌、抗病毒、抗炎、抗肿瘤、酶抑制剂、化学核酸酶等方面具有多种潜在优势，并且对铜类风湿性关节炎和胃溃疡等多种疾病也有益处(Fricker, S.P, Dalton Trans. 2007, 43, 4903-4917)。研究了方形平面[CuCl2(en)]和方形锥体[CuCl2(terpy)]配合物(其中en= 1,2-二氨基乙烷，terpy= 2,2′:6′，2′-三吡啶)与生物相关亲核试剂在pH 7.4、0.010 M NaCl存在下的取代反应。通过摩尔比、动力学、质谱和EPR研究对取代机理进行了探讨。在过量氯离子存在的情况下，八面体阴离子络合物[CuCl4(en)]2-迅速形成，而[CuCl2(terpy)]则观察到平衡反应。所选生物分子对Cu(II)配合物的反应性有不同的顺序。缓冲液的性质只影响Cu(II)配合物的构象动力学。根据EPR数据，在考虑的生物配体中，l -蛋氨酸与[CuCl2(en)]形成最稳定的配合物，而[CuCl2(terpy)]配合物非常稳定，并且在缓冲液或生物配体存在下其方锥体几何形状没有明显变化。这些结果代表了Cu(II)配合物与生物相关亲核试剂之间取代反应机理的研究进展。此外，它们为未来设计潜在的铜基抗癌药物提供了非常有用的信息(Selimovic, E.， et al.)。[j] .化学学报，2018,71(7)，1003-1019。
{"title":"Impact of different geometrical structures of copper(II) complexes on interactions with bio-relevant nucleophiles under physiological conditions","authors":"Enisa Selimović, A. Komolkin, A. Egorov, T. Soldatović","doi":"10.3390/ECMC-4-05479","DOIUrl":"https://doi.org/10.3390/ECMC-4-05479","url":null,"abstract":"Over the past decades, transition metal complexes have attracted considerable attention in medicinal inorganic chemistry, especially as synthetic metallonucleases and metal-based anticancer drugs that are able to bind to DNA under physiological conditions (Pessoa, J.C., et al. J. Inorg. Biochem. 2011, 105, 637-644). Copper(II) complexes offer various potential advantages as antimicrobial, antiviral, anti-inflammatory, antitumor agents, enzyme inhibitors, chemical nucleases, and they are also beneficial against several diseases like copper rheumatoid and gastric ulcers (Fricker, S.P., Dalton Trans. 2007, 43, 4903-4917).\u0000Substitution reactions of square-planar [CuCl2(en)] and square-pyramidal [CuCl2(terpy)] complexes (where en= 1,2-diaminoethane and terpy= 2,2’:6’,2’’- terpyridine) with bio-relevant nucleophiles have been investigated at pH 7.4 in the presence of 0.010 M NaCl. Mechanism of substitution was probed via mole-ratio, kinetic, mass spectroscopy and EPR studies. In the presence of an excess of chloride, the octahedral complex anion [CuCl4(en)]2- forms rapidly while equilibrium reaction was observed for [CuCl2(terpy)]. Different order of reactivity of selected bio-molecules toward Cu(II) complexes was observed. The nature of the buffer just affects the Cu(II) complexes conformational dynamics. According to EPR data L-Methionine forms a most stable complex with [CuCl2(en)] among the bio-ligands considered while [CuCl2(terpy)] complex is very stable and there are no significant changes in its square-pyramidal geometry in the presence of buffers or bio-ligands. The obtained results represent progress in investigation of the mechanism of substitution reactions between Cu(II) complexes and biological relevant nuclepohiles. Also, they provide very useful information for the future design of potential copper-based anticancer drugs (Selimovic, E., et al. J. Coord. Chem. 2018, 71(7), 1003-1019).","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91494273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：