QSAR-Based Virtual Screening: Advances and Applications in Drug Discovery

Virtual screening (VS) has emerged in drug discovery as a powerful computational approach to screen large libraries of small molecules for new hits with desired properties that can then be tested experimentally. Similar to other computational approaches, VS intention is not to replace in vitro or in vivo assays, but to speed up the discovery process, to reduce the number of candidates to be tested experimentally, and to rationalize their choice. Moreover, VS has become very popular in pharmaceutical companies and academic organizations due to its time-, cost-, resources-, and labor-saving. Among the VS approaches, quantitative structure–activity relationship (QSAR) analysis is the most powerful method due to its high and fast throughput and good hit rate. As the first preliminary step of a QSAR model development, relevant chemogenomics data are collected from databases and the literature. Then, chemical descriptors are calculated on different levels of representation of molecular structure, ranging from 1D to nD, and then correlated with the biological property using machine learning techniques. Once developed and validated, QSAR models are applied to predict the biological property of novel compounds. Although the experimental testing of computational hits is not an inherent part of QSAR methodology, it is highly desired and should be performed as an ultimate validation of developed models. In this mini-review, we summarize and critically analyze the recent trends of QSAR-based VS in drug discovery and demonstrate successful applications in identifying perspective compounds with desired properties. Moreover, we provide some recommendations about the best practices for QSAR-based VS along with the future perspectives of this approach

QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents

ATLANTIC EPIPHYTES: a data set of vascular and non-vascular epiphyte plants and lichens from the Atlantic Forest

Epiphytes are hyper-diverse and one of the frequently undervalued life forms in plant surveys and biodiversity inventories. Epiphytes of the Atlantic Forest, one of the most endangered ecosystems in the world, have high endemism and radiated recently in the Pliocene. We aimed to (1) compile an extensive Atlantic Forest data set on vascular, non-vascular plants (including hemiepiphytes), and lichen epiphyte species occurrence and abundance; (2) describe the epiphyte distribution in the Atlantic Forest, in order to indicate future sampling efforts. Our work presents the first epiphyte data set with information on abundance and occurrence of epiphyte phorophyte species. All data compiled here come from three main sources provided by the authors: published sources (comprising peer-reviewed articles, books, and theses), unpublished data, and herbarium data. We compiled a data set composed of 2,095 species, from 89,270 holo/hemiepiphyte records, in the Atlantic Forest of Brazil, Argentina, Paraguay, and Uruguay, recorded from 1824 to early 2018. Most of the records were from qualitative data (occurrence only, 88%), well distributed throughout the Atlantic Forest. For quantitative records, the most common sampling method was individual trees (71%), followed by plot sampling (19%), and transect sampling (10%). Angiosperms (81%) were the most frequently registered group, and Bromeliaceae and Orchidaceae were the families with the greatest number of records (27,272 and 21,945, respectively). Ferns and Lycophytes presented fewer records than Angiosperms, and Polypodiaceae were the most recorded family, and more concentrated in the Southern and Southeastern regions. Data on non-vascular plants and lichens were scarce, with a few disjunct records concentrated in the Northeastern region of the Atlantic Forest. For all non-vascular plant records, Lejeuneaceae, a family of liverworts, was the most recorded family. We hope that our effort to organize scattered epiphyte data help advance the knowledge of epiphyte ecology, as well as our understanding of macroecological and biogeographical patterns in the Atlantic Forest. No copyright restrictions are associated with the data set. Please cite this Ecology Data Paper if the data are used in publication and teaching events. © 2019 The Authors. Ecology © 2019 The Ecological Society of Americ

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.

Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization

QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium, affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum (PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as PfdUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual PfdUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity

Desempenho de pontas de pulverização em Brachiaria brizantha cv. MG-4 para controle de ninfas de cigarrinhas das pastagens Spray nozzles performance in Brachiaria brizantha cv. MG-4 for pastures spittlebugs nymphs control

O trabalho teve como objetivo estudar o desempenho de pontas de pulverização na deposição da calda inseticida para o controle de ninfas de cigarrinhas das pastagens em Brachiaria brizantha cv. MG-4. Doze tratamentos foram estudados em esquema fatorial 6x2, constituídos pelo contraste de seis pontas de pulverização e pressões de 196 e 392 kPa: TF-VP2 (336 L ha-1 e 467 L ha-1); AI11002-VS (184 L ha-1 e 200 L ha-1); XR11002-VS (200 L ha-1 e 280 L ha-1); TT11002-VP (200 L ha-1 e 280 L ha-1); TJ60-11002VS (208 L ha-1 e 280 L ha-1) e TX-VK4 (72 L ha-1 e 97 L ha-1). Para monitorar a deposição das caldas de pulverização, utilizaram-se os traçadores Azul Brilhante FD&C-1 (0,3% p/v) e Amarelo de Tartrasina FD&C-5 (0,6% p/v). Alvos artificiais, constituídos de lâminas de vidro, foram posicionados na base das plantas, próximos à superfície do solo, e os depósitos por unidade de área das soluções pulverizadas foram quantificados por espectrofotometria. As pontas TF-VP2, XR11002-VS e AI11002-VS, nas pressões de 196 e 392 kPa, proporcionam as maiores deposições da calda de pulverização na região das espumas das cigarrinhas das pastagens, apesar de apresentarem menor uniformidade na distribuição dos depósitos em relação a TX-VK4, XR110.02-VS e TJ110.02-VS. O aumento da pressão de 196 para 392 kPa promoveu aumento na deposição da calda de pulverização sobre a Brachiaria brizantha e na região onde se encontram as espumas das cigarrinhas para todos os tipos de pontas estudadas.<br>The work aimed to study spray nozzles performance in pesticide sprayer deposition for controlling pastures spittlebugs nymphs in Brachiaria brizantha cv. MG-4 pasture. Twelve treatments were studied in factorial scheme 6x2, constituted by the contrast of six spray nozzles and 196 and 392 kPa work pressures: TF-VP2 (336 L ha-1 and 467 L ha-1); AI11002-VS (184 L ha-1 and 200 L ha-1); XR11002-VS (200 L ha-1 and 280 L ha-1); TT11002-VP (200 L ha-1 and 280 L ha¹); TJ60-11002VS (208 L ha-1 and 280 L ha-1) and TX-VK4 (72 L ha-1 and 97 L ha-1). For monitoring sprayer deposition it was used Bright Blue FD&C-1 (0.3% p/v) and Tartrasine Yellow FD&C-5 (0.6% p/v) as tracers. Artificial targets, constituted by thin glass plates were positioned on plants tillers base, near to soil surface and deposition per unit area of sprayed solutions were quantified by spectrophotometry. TF-VP2; XR11002-VS and AI11002-VS spray nozzles, in 196 and 392 kPa work pressures provided the largest sprayer deposition in the foam regions of pastures spittlebugs nymph, in spite of showing inferior uniformities of sprayer deposition in relation to TX-VK4, XR110.02-VS and TJ110.02-VS.The increase of work pressure from 196 to 392 kPa promoted the increase of sprayer deposition over Brachiaria brizantha and over the region where pastures spittlebugs foams were located for all types of spray nozzles studied