Target-Based Evaluation of "Drug-Like" Properties and Ligand Efficiencies.
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ABSTRACT:
SUBMITTER: Leeson PD
PROVIDER: S-EPMC7610969 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite recent advances in bioinformatics, systems biology, and machine learning, the accurate prediction of drug properties remains an open problem. Indeed, because the biological environment is a complex system, the traditional approach-based on knowledge about the chemical structures-can not fully explain the nature of interactions between drugs and biological targets. Consequently, in this paper, we propose an unsupervised machine learning approach that uses the information we know about drug-target interactions to infer drug properties. To this end, we define drug similarity based on drug-target interactions and build a weighted Drug-Drug Similarity Network according to the drug-drug similarity relationships. Using an energy-model network layout, we generate drug communities associated with specific, dominant drug properties. DrugBank confirms the properties of 59.52% of the drugs in these communities, and 26.98% are existing drug repositioning hints we reconstruct with our DDSN approach. The remaining 13.49% of the drugs seem not to match the dominant pharmacologic property; thus, we consider them potential drug repurposing hints. The resources required to test all these repurposing hints are considerable. Therefore we introduce a mechanism of prioritization based on the betweenness/degree node centrality. Using betweenness/degree as an indicator of drug repurposing potential, we select Azelaic acid and Meprobamate as a possible antineoplastic and antifungal, respectively. Finally, we use a test procedure based on molecular docking to analyze Azelaic acid and Meprobamate's repurposing.
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Project description:Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein's sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein's sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins' hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme.
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Project description:Chemical fragment cosolvent sampling techniques have become a versatile tool in ligand-protein binding prediction. Site-identification by ligand competitive saturation (SILCS) is one such method that maps the distribution of chemical fragments on a protein as free energy fields called FragMaps. Ligands are then simulated via Monte Carlo techniques in the field of the FragMaps (SILCS-MC) to predict their binding conformations and relative affinities for the target protein. Application of SILCS-MC using a number of different scoring schemes and MC sampling protocols against multiple protein targets was undertaken to evaluate and optimize the predictive capability of the method. Seven protein targets and 551 ligands with broad chemical variability were used to evaluate and optimize the model to maximize Pearson's correlation coefficient, Pearlman's predictive index, correct relative binding affinity, and root-mean-square error versus the absolute experimental binding affinities. Across the protein-ligand sets, the relative affinities of the ligands were predicted correctly an average of 69% of the time for the highest overall SILCS protocol. Training the FragMap weighting factors using a Bayesian machine learning (ML) algorithm led to an increase to an average 75% relative correct affinity predictions. Furthermore, once the optimal protocol is identified for a specific protein-ligand system average predictabilities of 76% are achieved. The ML algorithm is successful with small training sets of data (30 or more compounds) due to the use of physically correct FragMap weights as priors. Notably, the 76% correct relative prediction rate is similar to or better than free energy perturbation methods that are significantly computationally more expensive than SILCS. The results further support the utility of SILCS as a powerful and computationally accessible tool to support lead optimization and development in drug discovery.
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Project description:To fight against the present pandemic scenario of COVID-19 outbreak, medication with drugs and vaccines is extremely essential other than ventilation support. In this paper, we present a list of ligands which are expected to have the highest binding affinity with the S-glycoprotein of 2019-nCoV and thus can be used to make the drug for the novel coronavirus. Here, we implemented an architecture using 1D convolutional networks to predict drug-target interaction (DTI) values. The network was trained on the KIBA (Kinase Inhibitor Bioactivity) dataset. With this network, we predicted the KIBA scores (which gives a measure of binding affinity) of a list of ligands against the S-glycoprotein of 2019-nCoV. Based on these KIBA scores, we are proposing a list of ligands (33 top ligands based on best interactions) which have a high binding affinity with the S-glycoprotein of 2019-nCoV and thus can be used for the formation of drugs.
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Project description:BackgroundDrugs that bind to common targets likely exert similar activities. In this target-centric view, the inclusion of richer target information may better represent the relationships between drugs and their activities. Under this assumption, we expanded the "common binding rule" assumption of QSAR to create a new drug-drug relationship score (DRS).MethodOur method uses various chemical features to encode drug target information into the drug-drug relationship information. Specifically, drug pairs were transformed into numerical vectors containing the basal drug properties and their differences. After that, machine learning techniques such as data cleaning, dimension reduction, and ensemble classifier were used to prioritize drug pairs bound to a common target. In other words, the estimation of the drug-drug relationship is restated as a large-scale classification problem, which provides the framework for using state-of-the-art machine learning techniques with thousands of chemical features for newly defining drug-drug relationships.ConclusionsVarious aspects of the presented score were examined to determine its reliability and usefulness: the abundance of common domains for the predicted drug pairs, c.a. 80% coverage for known targets, successful identifications of unknown targets, and a meaningful correlation with another cutting-edge method for analyzing drug similarities. The most significant strength of our method is that the DRS can be used to describe phenotypic similarities, such as pharmacological effects.
| S-EPMC3287478 | biostudies-literature
Project description:To deliver more therapeutics to more patients more quickly and economically is the ultimate goal of pharmaceutical researchers. The advent and rapid development of artificial intelligence (AI), in combination with other powerful computational methods in drug discovery, makes this goal more practical than ever before. Here, we describe a new strategy, retro drug design, or RDD, to create novel small-molecule drugs from scratch to meet multiple predefined requirements, including biological activity against a drug target and optimal range of physicochemical and ADMET properties. The molecular structure was represented by an atom typing based molecular descriptor system, optATP, which was further transformed to the space of loading vectors from principal component analysis. Traditional predictive models were trained over experimental data for the target properties using optATP and shallow machine learning methods. The Monte Carlo sampling algorithm was then utilized to find the solutions in the space of loading vectors that have the target properties. Finally, a deep learning model was employed to decode molecular structures from the solutions. To test the feasibility of the algorithm, we challenged RDD to generate novel kinase inhibitors from random numbers with five different ADMET properties optimized at the same time. The best Tanimoto similarity score between the generated valid structures and the available 4,314 kinase inhibitors was < 0.50, indicating a high extent of novelty of the generated compounds. From the 3,040 structures that met all six target properties, 20 were selected for synthesis and experimental measurement of inhibition activity over 97 representative kinases and the ADMET properties. Fifteen and eight compounds were determined to be hits or strong hits, respectively. Five of the six strong kinase inhibitors have excellent experimental ADMET properties. The results presented in this paper illustrate that RDD has the potential to significantly improve the current drug discovery process.
| S-EPMC9198977 | biostudies-literature
Project description:Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands, and the full complement of proteins with potential to be targeted by small molecules remains unknown. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We advance this knowledge to create ligands that affect the activity of proteins heretofore lacking chemical probes and to identify by phenotypic screening small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.
2017-01-24 | GSE90731 | GEO
Project description:Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3.
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Project description:Ligand-based and structure-based drug screening methods were integrated for in silico drug development by combining the maximum-volume overlap (MVO) method with a protein-compound docking program. The MVO method is used to select reliable docking poses by calculating volume overlaps between the docking pose in question and the known ligand docking pose, if at least a single protein-ligand complex structure is known. In the present study, the compounds in a database were docked onto a target protein that had a known protein-ligand complex structure. The new score is the summation of the docking score and the MVO score, which is the measure of the volume overlap between the docking poses of the compound in question and the known ligand. The compounds were sorted according to the new score. The in silico screening results were improved by comparing the MVO score to the original docking score only. The present method was also applied to some target proteins with known ligands, and the results demonstrated that it worked well.
| S-EPMC3816669 | biostudies-literature
Project description:BackgroundComputational approaches in the identification of drug targets are expected to reduce time and effort in drug development. Advances in genomics and proteomics provide the opportunity to uncover properties of druggable genomes. Although several studies have been conducted for distinguishing drug targets from non-drug targets, they mainly focus on the sequences and functional roles of proteins. Many other properties of proteins have not been fully investigated.MethodsUsing the DrugBank (version 3.0) database containing nearly 6,816 drug entries including 760 FDA-approved drugs and 1822 of their targets and human UniProt/Swiss-Prot databases, we defined 1578 non-redundant drug target and 17,575 non-drug target proteins. To select these non-redundant protein datasets, we built four datasets (A, B, C, and D) by considering clustering of paralogous proteins.ResultsWe first reassessed the widely used properties of drug target proteins. We confirmed and extended that drug target proteins (1) are likely to have more hydrophobic, less polar, less PEST sequences, and more signal peptide sequences higher and (2) are more involved in enzyme catalysis, oxidation and reduction in cellular respiration, and operational genes. In this study, we proposed new properties (essentiality, expression pattern, PTMs, and solvent accessibility) for effectively identifying drug target proteins. We found that (1) drug targetability and protein essentiality are decoupled, (2) druggability of proteins has high expression level and tissue specificity, and (3) functional post-translational modification residues are enriched in drug target proteins. In addition, to predict the drug targetability of proteins, we exploited two machine learning methods (Support Vector Machine and Random Forest). When we predicted drug targets by combining previously known protein properties and proposed new properties, an F-score of 0.8307 was obtained.ConclusionsWhen the newly proposed properties are integrated, the prediction performance is improved and these properties are related to drug targets. We believe that our study will provide a new aspect in inferring drug-target interactions.
| S-EPMC5471946 | biostudies-literature