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The human ether-à-go-go-related potassium channel (hERG) is a voltage-gated potassium channel involved in the repolarization of the cardiac action potential. The off-target inhibition of hERG is the most frequent cause of drug-induced cardiotoxicity. Therefore, assessing hERG related cardiotoxicity in the early phase of the drug discovery process is crucial to avoid undesired cardiotoxic effects. For this purpose, we developed several machine learning classification models for hERG liability profiling basing on Random Forest algorithm by means of Weka software. The models were trained on a dataset of molecules collected from the public repository ChEMBL (https://www.ebi.ac.uk/chembl/) and the commercial GOSTAR database (https://www.gostardb.com/). The training molecules were encoded by both ligand- and structure-based attributes. The former consist of a set of physicochemical descriptors and fingerprints computed by RDKit node available in KNIME, while the latter comprise different scores obtained by docking and rescoring calculations performed by LiGen and Rescore+ tools, respectively. The following models are made available: hERG_LB, trained on ligand-based descriptors hERG_LiGen_AV, trained on a set of scores computed on the docking poses yielded by LiGen, considering for each score the mean value over all the computed poses. hERG_LiGen_AV-LB, trained on the combination of the descriptors used to build hERG_LB and hERG_LiGen_AV-LB models. The input datasets used for the models training and evaluation are made available too. &nbsp

Nowadays there is a big spotlight cast on the development of techniques of explainable machine learning. Here we introduce a new computational paradigm based on Group Equivariant Non-Expansive Operators, that can be regarded as the product of a rising mathematical theory of information-processing observers. This approach, that can be adjusted to different situations, may have many advantages over other common tools, like Neural Networks, such as: knowledge injection and information engineering, selection of relevant features, small number of parameters and higher transparency. We chose to test our method, called GENEOnet, on a key problem in drug design: detecting pockets on the surface of proteins that can host ligands. Experimental results confirmed that our method works well even with a quite small training set, providing thus a great computational advantage, while the final comparison with other state-of-the-art methods shows that GENEOnet provides better or comparable results in terms of accuracy.

Antibiotic resistance is a major threat to global public health. β-lactamases, which catalyze breakdown of β-lactam antibiotics, are a principal cause. Metallo β-lactamases (MBLs) represent a particular challenge because they hydrolyze almost all β-lactams and to date no MBL inhibitor has been approved for clinical use. Molecular simulations can aid drug discovery, for example, predicting inhibitor complexes, but empirical molecular mechanics (MM) methods often perform poorly for metalloproteins. Here we present a multiscale approach to model thiol inhibitor binding to IMP-1, a clinically important MBL containing two catalytic zinc ions, and predict the binding mode of a 2-mercaptomethyl thiazolidine (MMTZ) inhibitor. Inhibitors were first docked into the IMP-1 active site, testing different docking programs and scoring functions on multiple crystal structures. Complexes were then subjected to molecular dynamics (MD) simulations and subsequently refined through QM/MM optimization with a density functional theory (DFT) method, B3LYP/6-31G(d), increasing the accuracy of the method with successive steps. This workflow was tested on two IMP-1:MMTZ complexes, for which it reproduced crystallographically observed binding, and applied to predict the binding mode of a third MMTZ inhibitor for which a complex structure was crystallographically intractable. We also tested a 12-6-4 nonbonded interaction model in MD simulations and optimization with a SCC-DFTB QM/MM approach. The results show the limitations of empirical models for treating these systems and indicate the need for higher level calculations, for example, DFT/MM, for reliable structural predictions. This study demonstrates a reliable computational pipeline that can be applied to inhibitor design for MBLs and other zinc-metalloenzyme systems.

Molecules : a journal of synthetic chemistry and natural product chemistry 26(4), 797 (2021). doi:10.3390/molecules26040797 special issue: "Computational Approaches: Drug Discovery and Design in Medicinal Chemistry and Bioinformatics / Special Issue Editors: Dr. Marco Tutone, Guest Editor; Prof. Dr. Anna Maria Almerico, Guest Editor", Published by Springer, Berlin ; Heidelberg

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies, (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines), such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs, (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection, and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.

O Projeto Esporte Brasil (PROESP-Br) propõe, desde 1994, uma bateria de medidas e testes para avaliação de escolares entre seis e 17 anos com o objetivo de delinear o perfil de crianças e jovens brasileiros no que se refere a aptidão física relacionada à saúde e ao desempenho motor. O objetivo deste estudo foi delinear o perfil da aptidão física de crianças e jovens brasileiros a partir de uma revisão sistemática da literatura sobre artigos que utilizaram da proposta do PROESP-Br. A busca foi realizada na PubMed, ScienceDirect, Lilacs, SciELO e Google Acadêmico. Estudos originais publicados entre 1994 e 2017 acerca da aptidão física (saúde e/ou desempenho motor) de escolares (crianças e/ou adolescentes) que utilizaram a bateria de testes do PROESP-Br foram incluídos. Um total de 13.582 sujeitos foram avaliados quanto a saúde e 276 quanto ao desempenho motor nos 18 estudos incluídos. A qualidade metodológica foi avaliada uma versão adaptada da Newcastle-Ottawa quality assessment scale. Os resultados evidenciam que 27-30% dos jovens estão na “zona de risco” à saúde para o Índice de Massa Corporal (IMC), 70% para a aptidão cardiorrespiratória (ApC) e 50 e 65% para flexibilidade e força muscular localizada (FML), respectivamente. Os dados sobre o desempenho motor são inconsistentes nesta revisão de literatura. Em síntese, os resultados indicam baixos níveis de saúde cardiovascular (IMC/ApC), principalmente quanto à ApC, assim como baixos níveis de saúde musculoesquelética (flexibilidade/FML) dos jovens. Ressalta-se a escassez de estudos quanto ao desempenho motor impossibilitando delinear o perfil dos componentes deste construto. Since 1994, the Projeto Esporte Brasil (PROESP-Br) battery tests has been used to evaluate healthand skill-related physical fitness among aged 6-17 Brazilian schoolchildren. The aim of this study was to delineate the Brazilian children and youth’s physical fitness profile from a systematic review over studies that used the PROESP-Br proposal. The search was carried at PubMed, ScienceDirect, Lilacs, SciELO and Google Scholar. Original studies published between 1994 and 2017 about physical fitness (health and/or motor performance) with schoolchildren (children and/or adolescents) that used the PROESP-Br battery test were included. A total of 13.582 participants were evaluated to health-related fitness and 276 to skill-related fitness from 18 included studies. The methodological quality was evaluated using the Newcastle-Ottawa quality assessment scale adapted version. The results show that 27-30% of youngsters are at health “risk zone” for Body Mass Index (BMI), 70% for cardiorespiratory fitness (CRF), 50% and 65% for flexibility (FLEX) and muscular strength (MST), respectively. The data concerning skill-related fitness were inconsistent. In summary, the results suggest that Brazilian children and adolescents have low cardiovascular health level (BMI/ CRF), mainly regarding CRF, and low muscle health level (FLEX/MST). We emphasize that the lack of studies regarding skill-related fitness, make it impossible to describe the profile of the components of this construct.

Malaria is an infectious disease caused by Plasmodium parasites. It results in an annual death-toll of ~ 600,000. Resistance to all medications currently in use exists, and novel antimalarial drugs are urgently needed. Plasmepsin V (PmV) is an essential Plasmodium protease and a highly promising antimalarial target, which still lacks molecular characterization and drug-like inhibitors. PmV, cleaving the PExEl motif, is the key enzyme for PExEl-secretion, an indispensable parasitic process for virulence and infection. Here, we describe the accessibility of PmV catalytic pockets to inhibitors and propose a novel strategy for PmV inhibition. We also provide molecular and structural data suitable for future drug development. Using high-throughput platforms, we identified a novel scaffold that interferes with PmV in-vitro at picomolar ranges (~ 1,000-fold more active than available compounds). Via systematic replacement of P and P' regions, we assayed the physico-chemical requirements for PmV inhibition, achieving an unprecedented IC50 of ~20 pM. The hydroxyethylamine moiety, the hydrogen acceptor group in P2', the lipophilic groups upstream to P3, the arginine and other possible substitutions in position P3 proved to be critically important elements in achieving potent inhibition. In-silico analyses provided essential QSAR information and model validation. Our inhibitors act 'on-target', confirmed by cellular interference of PmV function and biochemical interaction with inhibitors. Our inhibitors are poorly performing against parasite growth, possibly due to poor stability of their peptidic component and trans-membrane permeability. The lowest IC50 for parasite growth inhibition was ~ 15 μM. Analysis of inhibitor internalization revealed important pharmacokinetic features for PExEl-based molecules. Our work disclosed novel pursuable drug design strategies for highly efficient PmV inhibition highlighting novel molecular elements necessary for picomolar activity against PmV. All the presented data are discussed in respect to human aspartic proteases and previously reported inhibitors, highlighting differences and proposing new strategies for drug development.

RESUMO: a inclusão de alunos com deficiência é prevista em lei e manter boas estruturas físicas e pedagógicas na escola é um ponto fundamental para que o acesso possa acontecer. A Educação Física faz parte desta inclusão e pode proporcionar grandes melhoras na qualidade de vida de alunos com deficiência. Este estudo teve como objetivo compreender as percepções do aluno com deficiência a respeito das aulas de Educação Física. Para isso foi realizada uma pesquisa de natureza qualitativa utilizando para coleta de dados uma entrevista semiestruturada a qual foi gravada, transcrita e posteriormente analisada. A amostra foi constituída de 20 alunos com deficiência matriculados em escolas regulares da cidade de Santos Dumont - MG. A partir das entrevistas, destacou-se a percepção do aluno com deficiência a respeito da Educação Física escolar; o entendimento deles quanto ao conceito de qualidade de vida; as melhoras proporcionadas na qualidade de vida através da Educação Física; as facilidades e as dificuldades nas aulas; e as questões concernentes à relação aluno/professor e aluno/aluno. Os resultados dessa pesquisa podem auxiliar a comunidade escolar e o professor de Educação Física a melhorarem a inclusão nas escolas regulares. Além disso, as percepções dos alunos com deficiência sobre as aulas podem ajudar o professor na busca de um ambiente melhor com aulas que atendam a todos e proporcionem uma melhor qualidade de vida. ABSTRACT: The inclusion of disabled students is based on the law and the adaptation of physical and pedagogical structure at school represents a key point in order to make the access happen. Physical education is a part of the social inclusion and can provide great improvements in quality of life of students with disabilities. This research aimed to verify the perception of the student with disabilities on physical education classes. Therefore, a qualitative research was carried out, using a semi structured interview to collect data. The interviews were recorded, transcribed and analyzed. The sample was constituted by 20 students with disabilities enrolled in general schools at Santos Dumont, Minas Gerais. From the interviews, we highlighted the perceptions of students with disabilities on physical education at school; their understanding about the concept of quality of life; the improvements provided in the quality of life through physical education; successes and difficulties in class; and issues concerning the relationship student/ teacher and student/student. The results of this research can help the educational community and the physical education teacher to improve the quality of inclusion in general schools. In addition, perceptions of students with disabilities about the lessons can help the teacher in the search for a better environment with classes that meet everyone's needs and provide a better of quality of life.

a inclusão de alunos com deficiência é prevista em lei e manter boas estruturas físicas e pedagógicas na escola é um ponto fundamental para que o acesso possa acontecer. A Educação Física faz parte desta inclusão e pode proporcionar grandes melhoras na qualidade de vida de alunos com deficiência. Este estudo teve como objetivo compreender as percepções do aluno com deficiência a respeito das aulas de Educação Física. Para isso foi realizada uma pesquisa de natureza qualitativa utilizando para coleta de dados uma entrevista semiestruturada a qual foi gravada, transcrita e posteriormente analisada. A amostra foi constituída de 20 alunos com deficiência matriculados em escolas regulares da cidade de Santos Dumont - MG. A partir das entrevistas, destacou-se a percepção do aluno com deficiência a respeito da Educação Física escolar; o entendimento deles quanto ao conceito de qualidade de vida; as melhoras proporcionadas na qualidade de vida através da Educação Física; as facilidades e as dificuldades nas aulas; e as questões concernentes à relação aluno/professor e aluno/aluno. Os resultados dessa pesquisa podem auxiliar a comunidade escolar e o professor de Educação Física a melhorarem a inclusão nas escolas regulares. Além disso, as percepções dos alunos com deficiência sobre as aulas podem ajudar o professor na busca de um ambiente melhor com aulas que atendam a todos e proporcionem uma melhor qualidade de vida. The inclusion of disabled students is based on the law and the adaptation of physical and pedagogical structure at school represents a key point in order to make the access happen. Physical education is a part of the social inclusion and can provide great improvements in quality of life of students with disabilities. This research aimed to verify the perception of the student with disabilities on physical education classes. Therefore, a qualitative research was carried out, using a semi structured interview to collect data. The interviews were recorded, transcribed and analyzed. The sample was constituted by 20 students with disabilities enrolled in general schools at Santos Dumont, Minas Gerais. From the interviews, we highlighted the perceptions of students with disabilities on physical education at school; their understanding about the concept of quality of life; the improvements provided in the quality of life through physical education; successes and difficulties in class; and issues concerning the relationship student/ teacher and student/student. The results of this research can help the educational community and the physical education teacher to improve the quality of inclusion in general schools. In addition, perceptions of students with disabilities about the lessons can help the teacher in the search for a better environment with classes that meet everyone's needs and provide a better of quality of life.

(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 30-phosphoadenosine-50- phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The KM, Vmax, and kcat values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an “induced-fit model” in the catalytic pocket.

The present study proposes a method for an in silico calculation of phospholipophilicity. Phospholipophilicity is intended as the measure of analyte affinity for phospholipids; it is currently assessed by HPLC measures of analyte retention on phosphatidylcholine-like stationary phases (IAM - Immobilized Artificial Membrane) resulting in log kW(IAM) values. Due to the amphipathic and electrically charged nature of phospholipids, retention on these stationary phases results from complex mechanisms, being affected not only by lipophilicity (as measured by n-octanol/aqueous phase partition coefficients, log P) but also by the occurrence of polar and/or electrostatic intermolecular interaction forces. Differently from log P, to date no method has been proposed for in silico calculation of log kW(IAM). The study is aimed both at shedding new light into the retention mechanism on IAM stationary phases and at offering a high-throughput method to achieve such values. A wide set of physico-chemical and topological properties were taken into account, yielding a robust final model including four in silico calculated parameters (lipophilicity, hydrophilic/lipophilic balance, molecular size, and molecule flexibility). The here presented model was based on the analysis of 205 experimentally determined values, taken from the literature and measured by a single research group to minimize the interlaboratory variability; such model is able to predict phospholipophilicity values on both the two IAM stationary phases to date marketed, i.e. IAM.PC.MG and IAM.PC.DD2, with a fairly good degree (r(2)=0.85) of accuracy. The present work allowed to the development of a free on-line service aimed at calculating log kW(IAM) values of any molecule included in the PubChem database, which is freely available at http://nova.disfarm.unimi.it/logkwiam.htm.