Journal of Computer-Aided Molecular Design最新文献

{"title":"MASSA Algorithm: an automated rational sampling of training and test subsets for QSAR modeling","authors":"Gabriel Corrêa Veríssimo,&nbsp;Simone Queiroz Pantaleão,&nbsp;Philipe de Olveira Fernandes,&nbsp;Jadson Castro Gertrudes,&nbsp;Thales Kronenberger,&nbsp;Kathia Maria Honorio,&nbsp;Vinícius Gonçalves Maltarollo","doi":"10.1007/s10822-023-00536-y","DOIUrl":"10.1007/s10822-023-00536-y","url":null,"abstract":"<div><p>QSAR models capable of predicting biological, toxicity, and pharmacokinetic properties were widely used to search lead bioactive molecules in chemical databases. The dataset’s preparation to build these models has a strong influence on the quality of the generated models, and sampling requires that the original dataset be divided into training (for model training) and test (for statistical evaluation) sets. This sampling can be done randomly or rationally, but the rational division is superior. In this paper, we present MASSA, a Python tool that can be used to automatically sample datasets by exploring the biological, physicochemical, and structural spaces of molecules using PCA, HCA, and K-modes. The proposed algorithm is very useful when the variables used for QSAR are not available or to construct multiple QSAR models with the same training and test sets, producing models with lower variability and better values for validation metrics. These results were obtained even when the descriptors used in the QSAR/QSPR were different from those used in the separation of training and test sets, indicating that this tool can be used to build models for more than one QSAR/QSPR technique. Finally, this tool also generates useful graphical representations that can provide insights into the data.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41094801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (–)-epicatechin","authors":"Martina Hrast Rambaher,&nbsp;Irena Zdovc,&nbsp;Nina Kočevar Glavač,&nbsp;Stanislav Gobec,&nbsp;Rok Frlan","doi":"10.1007/s10822-023-00535-z","DOIUrl":"10.1007/s10822-023-00535-z","url":null,"abstract":"<div><p>MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (–)-epicatechin as MurF inhibitors with IC₅₀ values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (–)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with <span>d</span>-Ala-<span>d</span>-Ala dipeptide and UM3DAP substrates. Furthermore, <i>in silico</i> analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (–)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.</p><h3>Graphical abstract</h3>\u0000 <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\u0000 </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41097969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The in silico identification of novel broad-spectrum antidotes for poisoning by organophosphate anticholinesterases","authors":"Sohaib Habiballah,&nbsp;Janice Chambers,&nbsp;Edward Meek,&nbsp;Brad Reisfeld","doi":"10.1007/s10822-023-00537-x","DOIUrl":"10.1007/s10822-023-00537-x","url":null,"abstract":"<div><p>Owing to their potential to cause serious adverse health effects, significant efforts have been made to develop antidotes for organophosphate (OP) anticholinesterases, such as nerve agents. To be optimally effective, antidotes must not only reactivate inhibited target enzymes, but also have the ability to cross the blood–brain barrier (BBB). Progress has been made toward brain-penetrating acetylcholinesterase reactivators through the development of a new group of substituted phenoxyalkyl pyridinium oximes. To help in the selection and prioritization of compounds for future synthesis and testing within this class of chemicals, and to identify candidate broad-spectrum molecules, an in silico framework was developed to systematically generate structures and screen them for reactivation efficacy and BBB penetration potential.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41098000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)","authors":"Anacleto Silva de Souza,&nbsp;Robson Francisco de Souza,&nbsp;Cristiane Rodrigues Guzzo","doi":"10.1007/s10822-023-00534-0","DOIUrl":"10.1007/s10822-023-00534-0","url":null,"abstract":"<div><p>Herein, we conducted simulations of trimeric Spike from several SARS-CoV-2 variants of concern (Delta and Omicron sub-variants BA.2, BA.5, and BQ.1) and investigated the mechanisms by which specific mutations confer resistance to neutralizing antibodies. We observed that the mutations primarily affect the cooperation between protein domains within and between protomers. The substitutions K417N and L452R expand hydrogen bonding interactions, reducing their interaction with neutralizing antibodies. By interacting with nearby residues, the K444T and N460K mutations in the Spike^BQ.1 variant potentially reduces solvent exposure, thereby promoting resistance to antibodies. We also examined the impact of D614G, P681R, and P681H substitutions on Spike protein structure that may be related to infectivity. The D614G substitution influences communication between a glycine residue and neighboring domains, affecting the transition between up- and -down RBD states. The P681R mutation, found in the Delta variant, enhances correlations between protein subunits, while the P681H mutation in Omicron sub-variants weakens long-range interactions that may be associated with reduced fusogenicity. Using a multiple linear regression model, we established a connection between inter-protomer communication and loss of sensitivity to neutralizing antibodies. Our findings underscore the importance of structural communication between protein domains and provide insights into potential mechanisms of immune evasion by SARS-CoV-2. Overall, this study deepens our understanding of how specific mutations impact SARS-CoV-2 infectivity and shed light on how the virus evades the immune system.</p><h3>Graphical abstract</h3>\u0000 <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\u0000 </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41097395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TeM-DTBA: time-efficient drug target binding affinity prediction using multiple modalities with Lasso feature selection","authors":"Tanya Liyaqat,&nbsp;Tanvir Ahmad,&nbsp;Chandni Saxena","doi":"10.1007/s10822-023-00533-1","DOIUrl":"10.1007/s10822-023-00533-1","url":null,"abstract":"<div><p>Drug discovery, especially virtual screening and drug repositioning, can be accelerated through deeper understanding and prediction of Drug Target Interactions (DTIs). The advancement of deep learning as well as the time and financial costs associated with conventional wet-lab experiments have made computational methods for DTI prediction more popular. However, the majority of these computational methods handle the DTI problem as a binary classification task, ignoring the quantitative binding affinity that determines the drug efficacy to their target proteins. Moreover, computational space as well as execution time of the model is often ignored over accuracy. To address these challenges, we introduce a novel method, called Time-efficient Multimodal Drug Target Binding Affinity (TeM-DTBA), which predicts the binding affinity between drugs and targets by fusing different modalities based on compound structures and target sequences. We employ the Lasso feature selection method, which lowers the dimensionality of feature vectors and speeds up the proposed model training time by more than 50%. The results from two benchmark datasets demonstrate that our method outperforms state-of-the-art methods in terms of performance. The mean squared errors of 18.8% and 23.19%, achieved on the KIBA and Davis datasets, respectively, suggest that our method is more accurate in predicting drug-target binding affinity.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41104275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Conformational energies of reference organic molecules: benchmarking of common efficient computational methods against coupled cluster theory","authors":"Ioannis Stylianakis,&nbsp;Nikolaos Zervos,&nbsp;Jenn-Huei Lii,&nbsp;Dimitrios A. Pantazis,&nbsp;Antonios Kolocouris","doi":"10.1007/s10822-023-00531-3","DOIUrl":"10.1007/s10822-023-00531-3","url":null,"abstract":"","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41100576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving the accuracy of the FMO binding affinity prediction of ligand-receptor complexes containing metals","authors":"R. Paciotti,&nbsp;A. Marrone,&nbsp;C. Coletti,&nbsp;N. Re","doi":"10.1007/s10822-023-00532-2","DOIUrl":"10.1007/s10822-023-00532-2","url":null,"abstract":"<div><p>Polarization and charge transfer strongly characterize the ligand-receptor interaction when metal atoms are present, as for the Au(I)-biscarbene/DNA G-quadruplex complexes. In a previous work (<i>J Comput Aided Mol Des</i>2022, 36, 851–866) we used the ab initio FMO2 method at the RI-MP2/6-31G* level of theory with the PCM [1] solvation approach to calculate the binding energy (<i>ΔE</i>^<i>FMO</i>) of two Au(I)-biscarbene derivatives, [Au(9-methylcaffein-8-ylidene)₂]⁺ and [Au(1,3-dimethylbenzimidazole-2-ylidene)₂]⁺, able to interact with DNA G-quadruplex motif. We found that <i>ΔE</i>^<i>FMO</i> and ligand-receptor pair interaction energies (<i>E</i>^<i>INT</i>) show very large negative values making the direct comparison with experimental data difficult and related this issue to the overestimation of the embedded charge transfer energy between fragments containing metal atoms. In this work, to improve the accuracy of the FMO method for predicting the binding affinity of metal-based ligands interacting with DNA G-quadruplex (Gq), we assess the effect of the following computational features: <i>(i)</i> the electron correlation, considering the Hartree–Fock (HF) and a post-HF method, namely RI-MP2; <i>(ii)</i> the two (FMO2) and three-body (FMO3) approaches; <i>(iii)</i> the basis set size (polarization functions and double-ζ vs. triple-ζ) and <i>(iv)</i> the embedding electrostatic potential (ESP). Moreover, the partial screening method was systematically adopted to simulate the solvent screening effect for each calculation. We found that the use of the ESP computed using the screened point charges for all atoms (ESP-SPTC) has a critical impact on the accuracy of both <i>ΔE</i>^<i>FMO</i> and <i>E</i>^<i>INT</i>, eliminating the overestimation of charge transfer energy and leading to energy values with magnitude comparable with typical experimental binding energies. With this computational approach, E^INT values describe the binding efficiency of metal-based binders to DNA Gq more accurately than <i>ΔE</i>^<i>FMO</i>. Therefore, to study the binding process of metal containing systems with the FMO method, the adoption of partial screening solvent method combined with ESP-SPCT should be considered. This computational protocol is suggested for FMO calculations on biological systems containing metals, especially when the adoption of the default ESP treatment leads to questionable results.\u0000</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41094051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring DrugCentral: from molecular structures to clinical effects","authors":"Liliana Halip,&nbsp;Sorin Avram,&nbsp;Ramona Curpan,&nbsp;Ana Borota,&nbsp;Alina Bora,&nbsp;Cristian Bologa,&nbsp;Tudor I. Oprea","doi":"10.1007/s10822-023-00529-x","DOIUrl":"10.1007/s10822-023-00529-x","url":null,"abstract":"<div><p>DrugCentral, accessible at https://drugcentral.org, is an open-access online drug information repository. It covers over 4950 drugs, incorporating structural, physicochemical, and pharmacological details to support drug discovery, development, and repositioning. With around 20,000 bioactivity data points, manual curation enhances information from several major digital sources. Approximately 724 mechanism-of-action (MoA) targets offer updated drug target insights. The platform captures clinical data: over 14,300 on- and off-label uses, 27,000 contraindications, and around 340,000 adverse drug events from pharmacovigilance reports. DrugCentral encompasses information from molecular structures to marketed formulations, providing a comprehensive pharmaceutical reference. Users can easily navigate basic drug information and key features, making DrugCentral a versatile, unique resource. Furthermore, we present a use-case example where we utilize experimentally determined data from DrugCentral to support drug repurposing. A minimum activity threshold <i>t</i> should be considered against novel targets to repurpose a drug. Analyzing 1156 bioactivities for human MoA targets suggests a general threshold of 1 µM: <i>t</i> = 6 when expressed as − log[Activity(M)]). This applies to 87% of the drugs. Moreover, <i>t</i> can be refined empirically based on water solubility (S): <i>t</i> = 3 − logS, for logS &lt; − 3. Alongside the drug repurposing classification scheme, which considers intellectual property rights, market exclusivity protections, and market accessibility, DrugCentral provides valuable data to prioritize candidates for drug repurposing programs efficiently.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10236569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel and potent InhA direct inhibitors by ensemble docking-based virtual screening and biological assays","authors":"Qianqian Zhang,&nbsp;Jianting Han,&nbsp;Yongchang Zhu,&nbsp;Fansen Yu,&nbsp;Xiaopeng Hu,&nbsp;Henry H. Y. Tong,&nbsp;Huanxiang Liu","doi":"10.1007/s10822-023-00530-4","DOIUrl":"10.1007/s10822-023-00530-4","url":null,"abstract":"<div><p>Multidrug-resistant tuberculosis (MDR-TB) continues to spread worldwide and remains one of the leading causes of death among infectious diseases. The enoyl-acyl carrier protein reductase (InhA) belongs to FAS-II family and is essential for the formation of the Mycobacterium tuberculosis cell wall. Recent years, InhA direct inhibitors have been extensively studied to overcome MDR-TB. However, there are still no inhibitors that have entered clinical research. Here, the ensemble docking-based virtual screening along with biological assay were used to identify potent InhA direct inhibitors from Chembridge, Chemdiv, and Specs. Ultimately, 34 compounds were purchased and first assayed for the binding affinity, of which four compounds can bind InhA well with K_D values ranging from 48.4 to 56.2 µM. Among them, compound 9,222,034 has the best inhibitory activity against InhA enzyme with an IC₅₀ value of 18.05 µM. In addition, the molecular dynamic simulation and binding free energy calculation indicate that the identified compounds bind to InhA with “extended” conformation. Residue energy decomposition shows that residues such as Tyr158, Met161, and Met191 have higher energy contributions in the binding of compounds. By analyzing the binding modes, we found that these compounds can bind to a hydrophobic sub-pocket formed by residues Tyr158, Phe149, Ile215, Leu218, etc., resulting in extensive van der Waals interactions. In summary, this study proposed an efficient strategy for discovering InhA direct inhibitors through ensemble docking-based virtual screening, and finally identified four active compounds with new skeletons, which can provide valuable information for the discovery and optimization of InhA direct inhibitors.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ChemFlow_py: a flexible toolkit for docking and rescoring","authors":"Luca Monari,&nbsp;Katia Galentino,&nbsp;Marco Cecchini","doi":"10.1007/s10822-023-00527-z","DOIUrl":"10.1007/s10822-023-00527-z","url":null,"abstract":"<div><p>The design of accurate virtual screening tools is an open challenge in drug discovery. Several structure-based methods have been developed at different levels of approximation. Among them, molecular docking is an established technique with high efficiency, but typically low accuracy. Moreover, docking performances are known to be target-dependent, which makes the choice of the docking program and corresponding scoring function critical when approaching a new protein target. To compare the performances of different docking protocols, we developed ChemFlow_py, an automated tool to perform docking and rescoring. Using four protein systems extracted from DUD-E with 100 known active compounds and 3000 decoys per target, we compared the performances of several rescoring strategies including consensus scoring. We found that the average docking results can be improved by consensus ranking, which emphasizes the relevance of consensus scoring when little or no chemical information is available for a given target. ChemFlow_py is a free toolkit to optimize the performances of virtual high-throughput screening (vHTS). The software is publicly available at https://github.com/IFMlab/ChemFlow_py.</p><h3>Graphical abstract</h3>\u0000 <figure><div><div><div><picture><source><img></source></picture></div></div></div></figure>\u0000 </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00527-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6727403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}