PeptoGrid—Rescoring Function for AutoDock Vina to Identify New Bioactive Molecules from Short Peptide Libraries

Peptides are promising drug candidates due to high specificity and standout safety. Identification of bioactive peptides de novo using molecular docking is a widely used approach. However, current scoring functions are poorly optimized for peptide ligands. In this work, we present a novel algorithm PeptoGrid that rescores poses predicted by AutoDock Vina according to frequency information of ligand atoms with particular properties appearing at different positions in the target protein’s ligand binding site. We explored the relevance of PeptoGrid ranking with a virtual screening of peptide libraries using angiotensin-converting enzyme and GABAB receptor as targets. A reasonable agreement between the computational and experimental data suggests that PeptoGrid is suitable for discovering functional leads.

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AAV-Mediated CRISPRi and RNAi Based Gene Silencing in Mouse Hippocampal Neurons

Cells ◽

10.3390/cells10020324 ◽

2021 ◽

Vol 10 (2) ◽

pp. 324

Author(s):

Matthias Deutsch ◽

Anne Günther ◽

Rodrigo Lerchundi ◽

Christine R. Rose ◽

Sabine Balfanz ◽

...

Keyword(s):

Gene Expression ◽

Transcription Initiation ◽

Hippocampal Neurons ◽

De Novo ◽

Protein Biosynthesis ◽

Physiological Role ◽

High Specificity ◽

Hcn Channels ◽

Proliferating Cells ◽

Neuronal Tissues

Uncovering the physiological role of individual proteins that are part of the intricate process of cellular signaling is often a complex and challenging task. A straightforward strategy of studying a protein’s function is by manipulating the expression rate of its gene. In recent years, the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9-based technology was established as a powerful gene-editing tool for generating sequence specific changes in proliferating cells. However, obtaining homogeneous populations of transgenic post-mitotic neurons by CRISPR/Cas9 turned out to be challenging. These constraints can be partially overcome by CRISPR interference (CRISPRi), which mediates the inhibition of gene expression by competing with the transcription machinery for promoter binding and, thus, transcription initiation. Notably, CRISPR/Cas is only one of several described approaches for the manipulation of gene expression. Here, we targeted neurons with recombinant Adeno-associated viruses to induce either CRISPRi or RNA interference (RNAi), a well-established method for impairing de novo protein biosynthesis by using cellular regulatory mechanisms that induce the degradation of pre-existing mRNA. We specifically targeted hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, which are widely expressed in neuronal tissues and play essential physiological roles in maintaining biophysical characteristics in neurons. Both of the strategies reduced the expression levels of three HCN isoforms (HCN1, 2, and 4) with high specificity. Furthermore, detailed analysis revealed that the knock-down of just a single HCN isoform (HCN4) in hippocampal neurons did not affect basic electrical parameters of transduced neurons, whereas substantial changes emerged in HCN-current specific properties.

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PEPstr: A de novo Method for Tertiary Structure Prediction of Small Bioactive Peptides

Protein and Peptide Letters ◽

10.2174/092986607781483859 ◽

2007 ◽

Vol 14 (7) ◽

pp. 626-631 ◽

Cited By ~ 133

Author(s):

Harpreet Kaur ◽

Aarti Garg ◽

G.P.S. Raghava

Keyword(s):

Structure Prediction ◽

Bioactive Peptides ◽

Tertiary Structure ◽

De Novo ◽

Tertiary Structure Prediction

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Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Topics in Current Chemistry ◽

10.1007/s41061-021-00347-5 ◽

2021 ◽

Vol 379 (5) ◽

Author(s):

Giovanna Li Petri ◽

Maria Valeria Raimondi ◽

Virginia Spanò ◽

Ralph Holl ◽

Paola Barraja ◽

...

Keyword(s):

Three Dimensional ◽

Binding Mode ◽

Biologically Active ◽

Bioactive Molecules ◽

Biological Profile ◽

Pyrrolidine Ring ◽

Reaction Conditions ◽

Drug Candidates ◽

Steric Factors ◽

Proline Derivatives

AbstractThe five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

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Incorporating structural similarity into a scoring function to enhance the prediction of binding affinities

Journal of Cheminformatics ◽

10.1186/s13321-021-00493-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Beihong Ji ◽

Xibing He ◽

Yuzhao Zhang ◽

Jingchen Zhai ◽

Viet Hoang Man ◽

...

Keyword(s):

Computational Cost ◽

Scoring Function ◽

Structural Similarity ◽

Scoring Functions ◽

Binding Affinities ◽

Autodock Vina ◽

Predictive Index ◽

Drug Lead ◽

Screening Performance ◽

Calibration Algorithm

AbstractIn this study, we developed a novel algorithm to improve the screening performance of an arbitrary docking scoring function by recalibrating the docking score of a query compound based on its structure similarity with a set of training compounds, while the extra computational cost is neglectable. Two popular docking methods, Glide and AutoDock Vina were adopted as the original scoring functions to be processed with our new algorithm and similar improvement performance was achieved. Predicted binding affinities were compared against experimental data from ChEMBL and DUD-E databases. 11 representative drug receptors from diverse drug target categories were applied to evaluate the hybrid scoring function. The effects of four different fingerprints (FP2, FP3, FP4, and MACCS) and the four different compound similarity effect (CSE) functions were explored. Encouragingly, the screening performance was significantly improved for all 11 drug targets especially when CSE = S4 (S is the Tanimoto structural similarity) and FP2 fingerprint were applied. The average predictive index (PI) values increased from 0.34 to 0.66 and 0.39 to 0.71 for the Glide and AutoDock vina scoring functions, respectively. To evaluate the performance of the calibration algorithm in drug lead identification, we also imposed an upper limit on the structural similarity to mimic the real scenario of screening diverse libraries for which query ligands are general-purpose screening compounds and they are not necessarily structurally similar to reference ligands. Encouragingly, we found our hybrid scoring function still outperformed the original docking scoring function. The hybrid scoring function was further evaluated using external datasets for two systems and we found the PI values increased from 0.24 to 0.46 and 0.14 to 0.42 for A2AR and CFX systems, respectively. In a conclusion, our calibration algorithm can significantly improve the virtual screening performance in both drug lead optimization and identification phases with neglectable computational cost.

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Capture-based enrichment of Theileria parva DNA enables full genome assembly of first buffalo-derived strain and reveals exceptional intra-specific genetic diversity

10.1101/2020.04.11.037309 ◽

2020 ◽

Author(s):

Nicholas C Palmateer ◽

Kyle Tretina ◽

Joshua Orvis ◽

Olukemi O Ifeonu ◽

Jonathan Crabtree ◽

...

Keyword(s):

Vaccine Development ◽

De Novo ◽

High Specificity ◽

Theileria Parva ◽

Nucleotide Polymorphisms ◽

Specificity And Sensitivity ◽

Genome Wide ◽

Dna Capture ◽

High Level ◽

Genome Assemblies

AbstractTheileria parva is an economically important, intracellular, tick-transmitted parasite of cattle. A live vaccine against the parasite is effective against challenge from cattle-transmissible T. parva but not against genotypes originating from the African Cape buffalo, a major wildlife reservoir, prompting the need to characterize genome-wide variation within and between cattle- and buffalo-associated T. parva populations. Here, we describe a capture-based target enrichment approach that enables, for the first time, de novo assembly of nearly complete T. parva genomes derived from infected host cell lines. This approach has exceptionally high specificity and sensitivity and is successful for both cattle- and buffalo-derived T. parva parasites. De novo genome assemblies generated for cattle genotypes differ from the reference by ∼54K single nucleotide polymorphisms (SNPs) throughout the 8.31 Mb genome, an average of 6.5 SNPs/kb. We report the first buffalo-derived T. parva genome, which is larger than the genome from the reference, cattle-derived, Muguga strain. The average non-synonymous nucleotide diversity (πN) per gene, between buffalo-derived T. parva and the Muguga strain, was 1.3%. This remarkably high level of genetic divergence is supported by an average FST, genome-wide, of 0.44, reflecting a degree of genetic differentiation between cattle- and buffalo-derived T. parva parasites more commonly seen between, rather than within, species, with clear implications for vaccine development. The DNA capture approach used provides clear advantages over alternative T. parva DNA enrichment methods used previously and enables in-depth comparative genomics in this apicomplexan parasite.

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Exploring the Boundaries of “Practical”: De Novo Syntheses of Complex Natural Product-Based Drug Candidates

Chemical Reviews ◽

10.1021/acs.chemrev.7b00126 ◽

2017 ◽

Vol 117 (18) ◽

pp. 11994-12051 ◽

Cited By ~ 33

Author(s):

Tyler K. Allred ◽

Francesco Manoni ◽

Patrick G. Harran

Keyword(s):

Natural Product ◽

De Novo ◽

Drug Candidates

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Identification of Antimicrobial Peptides from the Microalgae Tetraselmis suecica (Kylin) Butcher and Bactericidal Activity Improvement

Marine Drugs ◽

10.3390/md17080453 ◽

2019 ◽

Vol 17 (8) ◽

pp. 453 ◽

Cited By ~ 8

Author(s):

Guzmán ◽

Wong ◽

Román ◽

Cárdenas ◽

Alvárez ◽

...

Keyword(s):

Antibacterial Activity ◽

Pathogenic Bacteria ◽

Bioactive Peptides ◽

De Novo ◽

Helical Structure ◽

Antimicrobial Activities ◽

Peptide Sequence ◽

Tetraselmis Suecica ◽

Defense Strategies ◽

Key Residues

The outburst of microbial resistance to antibiotics creates the need for new sources of active compounds for the treatment of pathogenic microorganisms. Marine microalgae are of particular interest in this context because they have developed tolerance and defense strategies to resist the exposure to pathogenic bacteria, viruses, and fungi in the aquatic environment. Although antimicrobial activities have been reported for some microalgae, natural algal bioactive peptides have not been described yet. In this work, acid extracts from the microalga Tetraselmis suecica with antibacterial activity were analyzed, and de novo sequences of peptides were determined. Synthetic peptides and their alanine and lysine analogs allowed identifying key residues and increasing their antibacterial activity. Additionally, it was determined that the localization of positive charges within the peptide sequence influences the secondary structure with tendency to form an alpha helical structure.

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Virtual screening web servers: designing chemical probes and drug candidates in the cyberspace

Briefings in Bioinformatics ◽

10.1093/bib/bbaa034 ◽

2020 ◽

Cited By ~ 8

Author(s):

Natesh Singh ◽

Ludovic Chaput ◽

Bruno O Villoutreix

Keyword(s):

Virtual Screening ◽

Drug Repositioning ◽

Pharmaceutical Research ◽

Bioactive Molecules ◽

Screening Methods ◽

Web Servers ◽

Web Based ◽

Drug Candidates ◽

Screening Experiments ◽

Molecule Docking

Abstract The interplay between life sciences and advancing technology drives a continuous cycle of chemical data growth; these data are most often stored in open or partially open databases. In parallel, many different types of algorithms are being developed to manipulate these chemical objects and associated bioactivity data. Virtual screening methods are among the most popular computational approaches in pharmaceutical research. Today, user-friendly web-based tools are available to help scientists perform virtual screening experiments. This article provides an overview of internet resources enabling and supporting chemical biology and early drug discovery with a main emphasis on web servers dedicated to virtual ligand screening and small-molecule docking. This survey first introduces some key concepts and then presents recent and easily accessible virtual screening and related target-fishing tools as well as briefly discusses case studies enabled by some of these web services. Notwithstanding further improvements, already available web-based tools not only contribute to the design of bioactive molecules and assist drug repositioning but also help to generate new ideas and explore different hypotheses in a timely fashion while contributing to teaching in the field of drug development.

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De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

Science ◽

10.1126/science.abe0075 ◽

2020 ◽

Vol 370 (6521) ◽

pp. 1208-1214 ◽

Cited By ~ 4

Author(s):

Thomas W. Linsky ◽

Renan Vergara ◽

Nuria Codina ◽

Jorgen W. Nelson ◽

Matthew J. Walker ◽

...

Keyword(s):

Protein Design ◽

De Novo ◽

High Specificity ◽

Spike Protein ◽

Host Proteins ◽

Angiotensin Converting Enzyme 2 ◽

Cryo Electron Microscopy ◽

De Novo Protein Design ◽

Single Spike

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo–electron microscopy (cryo-EM) showed that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized SARS-CoV-2 infection of cells in vitro, and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.

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