Homology modeling, molecular dynamics and docking simulations of rat A2A receptor: a three-dimensional model validation under QSAR studies

Understanding the three-dimensional structure (3-D) of GPCRs (G protein coupled receptors) can aid in the design of applicable compounds for the treatment of several human disorders. To this end, several 3-D models have been obtained in recent years. In this work, we have built the rat adenosine receptor model (rA2AR) by employing computational tools. First, the 3-D rA2AR model was built by homology modeling using the human adenosine receptor (hA2AR) structure (PDB codes: 3EML) as a template. Then, the rA2AR model was refined by molecular dynamics simulations, in which the initial and refined 3-D structures were used for molecular docking simulations and Quantitative structure-activity relationship (QSAR) studies using a set of known experimentally tested ligands to validate this rA2AR model. The results showed that the hindrance effect caused by ribose attached to agonists play an important role in activating the receptor via formation of several hydrogen bonds. In contrast, the lack of this moiety allows blocking of the receptor. The theoretical affinity estimation shows good correlation with reported experimental data. Therefore, this work represents a good example for getting reliable GPCR models under computational procedures.We are grateful for the scholarships and financial support from CONACYT, México (132353), ICyTDF (PIRIVI09-9), COFAA and SIP-IPN (20110786), PAPIIT-DGAPA UNAM-215708 and Posgrado en Ciencias Biológicas UNAM. The authors thank the Centro Nacional de Supercomputo, México, for providing access to the “Argentum” cluster

2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure-activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation

Diseño, síntesis y evaluación quimico-farmacodinamica de compuestos con acción sobre el receptor beta-2 adrenérgico

Tesis (Maestría en Ciencias en Farmacología), Instituto Politécnico Nacional, SEPI, ESM, 2009, 1 archivo PDF, (61 páginas). tesis.ipn.m

Theoretical Evaluation of Bortezomib and Other Boron-Containing Compounds as Inhibitors of SARS-CoV-2 Main Protease

The aim of the present docking study was to explore the putative role of boronic moieties in molecules interacting on the binding site of the SARS-CoV-2 main protease. The methodology was based on the conventional docking procedure by means of AutoDock software by assaying boron-free and boron-containing compounds on the recent reported crystal structure of SARS-CoV-2 main protease (PDB code: 6LU7). The most of tested compounds share contact with key residues and poses on the cleavage pocket. Those compounds with a boron atom in its structure often were estimated with higher affinity than boron-free analogues. Interactions and affinity of boron-containing peptidomimetics on the binding site let us to propose the potent inhibition of these compounds on targeted protease. These advances may be relevant for drug designing, but also to suggest the testing of available boron-containing drugs in patients with severe symptoms of COVID19 infection

Genotype-phenotype discordance in a duchenne muscular dystrophy patient due to a novel mutation: Insights into the shock absorber function of dystrophin [Discordancia genotipo-fenotipo en un paciente con distrofia muscular de duchenne por una nueva mutaci�n: Hip�tesis de la funci�n de amortiguaci�n de la distrofina]

Introduction. Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. Case report. We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. Conclusions. Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD

[Genotype-phenotype discordance in a Duchenne muscular dystrophy patient due to a novel mutation: insights into the shock absorber function of dystrophin]

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. CASE REPORT: We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. CONCLUSIONS: Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD

[Genotype-phenotype discordance in a Duchenne muscular dystrophy patient due to a novel mutation: insights into the shock absorber function of dystrophin]

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. CASE REPORT: We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. CONCLUSIONS: Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD

Genotype-phenotype discordance in a duchenne muscular dystrophy patient due to a novel mutation: Insights into the shock absorber function of dystrophin [Discordancia genotipo-fenotipo en un paciente con distrofia muscular de duchenne por una nueva mutación: Hipótesis de la función de amortiguación de la distrofina]

Introduction. Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. Case report. We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. Conclusions. Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD