Fine tuning for success in structure-based virtual screening.

Structure-based virtual screening plays a significant role in drug-discovery. The method virtually docks millions of compounds from corporate or public libraries into a binding site of a disease-related protein structure, allowing for the selection of a small list of potential ligands for experimental testing. Many algorithms are available for docking and assessing the affinity of compounds for a targeted protein site. The performance of affinity estimation calculations is highly dependent on the size and nature of the site, therefore a rationale for selecting the best protocol is required. To address this issue, we have developed an automated calibration process, implemented in a Knime workflow. It consists of four steps: preparation of a protein test set with structures and models of the target, preparation of a compound test set with target-related ligands and decoys, automatic test of 24 scoring/rescoring protocols for each target structure and model, and graphical display of results. The automation of the process combined with execution on high performance computing resources greatly reduces the duration of the calibration phase, and the test of many combinations of algorithms on various target conformations results in a rational and optimal choice of the best protocol. Here, we present this tool and exemplify its application in setting-up an optimal protocol for SBVS against Retinoid X Receptor alpha.

Artificial Intelligence, Machine Learning, and Deep Learning in Real-Life Drug Design Cases.

The discovery and development of drugs is a long and expensive process with a high attrition rate. Computational drug discovery contributes to ligand discovery and optimization, by using models that describe the properties of ligands and their interactions with biological targets. In recent years, artificial intelligence (AI) has made remarkable modeling progress, driven by new algorithms and by the increase in computing power and storage capacities, which allow the processing of large amounts of data in a short time. This review provides the current state of the art of AI methods applied to drug discovery, with a focus on structure- and ligand-based virtual screening, library design and high-throughput analysis, drug repurposing and drug sensitivity, de novo design, chemical reactions and synthetic accessibility, ADMET, and quantum mechanics.

User-Friendly Quantum Mechanics: Applications for Drug Discovery.

Quantum mechanics (QM) methods provide a fine description of receptor-ligand interactions and of chemical reactions. Their use in drug design and drug discovery is increasing, especially for complex systems including metal ions in the binding sites, for the design of highly selective inhibitors, for the optimization of bi-specific compounds, to understand enzymatic reactions, and for the study of covalent ligands and prodrugs. They are also used for generating molecular descriptors for predictive QSAR/QSPR models and for the parameterization of force fields. Thanks to the continuous increase of computational power offered by GPUs and to the development of sophisticated algorithms, QM methods are becoming part of the standard tools used in computer-aided drug design (CADD). We present the most used QM methods and software packages, and we discuss recent representative applications in drug design and drug discovery.

Seroprevalence of Trypanosoma cruzi Infection in Pregnant Women Suggests a High Risk for Congenital Transmission in Central Veracruz, Mexico.

PURPOSE: The state of Veracruz, Mexico, is a well-recognized endemic region for Chagas disease, but congenital transmission has not been extensively studied. We estimated here the prevalence and the risk of congenital transmission of Trypanosoma cruzi in pregnant women from 27 municipalities of central Veracruz. METHODS: 528 sera from pregnant women were analyzed by ELISA and IFA assays for the detection of IgG antibodies against T. cruzi. RESULTS: The presence of anti-T. cruzi antibodies was identified in women from 17 municipalities, obtaining an overall seroprevalence of 17.0%. A higher seropositivity was observed in the municipalities of Orizaba (25.2%), Nogales (13.6%), and Río Blanco (10.5%). The results suggest that there is a high risk of congenital transmission of T. cruzi in the region. CONCLUSION: There are currently limited actions for the surveillance and control of congenital transmission of Chagas disease in Veracruz.

Bactericidal Disruption of Magnesium Metallostasis in Mycobacterium tuberculosis Is Counteracted by Mutations in the Metal Ion Transporter CorA.

A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds' cidality against replicating M. tuberculosis These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds.IMPORTANCE Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg2+/Co2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg2+-deficient intraphagosomal environment of macrophages.

Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke.

OBJECTIVE: To evaluate the feasibility of monitoring the autologous mononuclear bone marrow (ABMMN) cells implanted into the brain after acute ischemic stroke by the technique of labeling with Tc-99m-HMPAO. CASE REPORT: A 37-year-old man presented with aphasia, right-side hypoesthesia, and right homonymous hemianopsia after an acute ischemic stroke of the left middle cerebral artery. He was included in an autologous bone marrow mononuclear cell-based therapy research protocol about the safety of intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Nine days after the stroke he received 3.0 x 10(7) ABMMN cells delivered into the left cerebral middle artery via a balloon catheter. Approximately 1% of these cells were labeled with 150 MBq (4 mCi) Tc-99m by incubation with hexamethylpropylene amine oxime (HMPAO). RESULTS: Brain perfusion images with Tc-99m ECD demonstrated hypoperfusion in the left temporal and parietal regions. The perfusion brain images were compared with tomographic views of the brain obtained 8 hours after ABMMN-labeled cell delivery, revealing intense accumulation of the ABMMN-labeled cells in the ipsilateral hemisphere. A whole-body scan was done and showed left brain, liver, and spleen uptake. CONCLUSIONS: Our results showed that Tc-99m HMPAO can be used to label ABMMN cells for in vivo cell visualization, and that brain SPECT imaging with labeled ABMMN cells is a feasible noninvasive method for studying the fate of transplanted cells in vivo. Additionally, our findings demonstrate the localization of these intra-arterially injected cells.