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Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected, based on the binding affinities, docking scores and selectivity. Further, binding energy calculation, Lipinski filtration and ADMET prediction were carried out to find safe and better hits against MARK4. Best 10 compounds bearing high specificity and binding efficiency were selected, and their binding pattern to MARK4 was analyzed in detail. Finally, 100 ns molecular dynamics simulation was performed to evaluate; the dynamics stability of MARK4-compound complex. In conclusion, these selected natural compounds from ZINC database might be potential leads against MARK4, and can further be exploited in drug design and development for associated diseases.

Background: Extracellular signal-regulated kinase 1 (ERK1) belongs to mitogen-activated protein kinases, which are essential for memory formation, cognitive function, and synaptic plasticity. During Alzheimer's disease (AD), ERK1 phosphorylates tau at 15 phosphorylation sites, leading to the formation of neurofibrillary tangles. The overactivation of ERK1 in microglia promotes the release of pro-inflammatory cytokines, which results in neuroinflammation. Additionally, elevated oxidative stress during AD stimulates the ERK1 pathway, leading to neuronal loss. Objective: Because ERK1 signaling plays a significant role in tau phosphorylation, targeting ERK1 may be therapeutically beneficial by either preventing excessive activation of the signaling pathway or altering its pathway to enhance neuroprotective effects during AD. Methods: This study employed structure-based virtual screening of phytoconstituents from the IMPPAT library. Subsequently, in-depth docking and molecular dynamics (MD) simulation studies were implemented to identify potential ERK1 inhibitors with desirable pharmacological properties. Results: Silandrin and Hydroxytuberosone were found to be potential ERK1 inhibitors with higher affinity and specificity than the control molecule Tizaterkib. These compounds specifically bind to the ERK1 substrate binding pocket and interact with crucial residues. Finally, the elucidated compounds with ERK1 were evaluated using an all-atom molecular MD simulation to analyze structural dynamics, structural compactness, hydrogen bond dynamics, principal component analysis, and free energy landscape. Conclusions: The study suggested that Silandrin and Hydroxytuberosone can further be exploited as potential lead molecules for therapeutic development against ERK1-mediated AD. [ABSTRACT FROM AUTHOR]

There is a growing interest in harnessing natural compounds and bioactive phytochemicals to accelerate drug discovery and development, including in the treatment of human cancers. Receptor tyrosine kinases (RTKs) are critical regulators of many fundamental cellular processes and have been implicated in cancer pathogenesis as well as targets for anticancer drug development. The members of TAM, Tyro3, Axl, and MERTK subfamily RTKs, especially Mer, affect immune homeostasis in the tumor microenvironment. Hence, tyrosine-protein kinase Mer has emerged as one of the key factors in cancer susceptibility and metastasis and, by extension, as a potential target of relevance for cancer drug resistance. Here, we report, using an integrated virtual screening and simulation of phytochemicals from the IMPPAT 2.0 library, phytochemicals withanolide N and dryobalanolide as potential bioactive leads for developing anticancer drugs targeting tyrosine-protein kinase Mer. The study employed an integrated design, including physicochemical property analyses, binding affinity calculations, pan-assay interference compounds filtering, absorption, distribution, metabolism, excretion, and toxicity, and PASS analyses, in silico molecular dynamics simulations, followed by principal component analysis and free energy landscape. We call for further evaluation, validation, and translational medical research on these two phytochemicals in vitro and in vivo, with an eye to their putative therapeutic efficacy and safety in the field of oncology and anticancer drug discovery and development. [ABSTRACT FROM AUTHOR]

Activin receptor‐like kinase 1 (ALK1) is a transmembrane receptor involved in crucial signaling pathways associated with angiogenesis and vascular development. Inhibition of ALK1 signaling has emerged as a promising therapeutic strategy for various angiogenesis‐related diseases, including cancer and hereditary hemorrhagic telangiectasia. This study aimed to investigate the potential of phytoconstituents as inhibitors of ALK1 using a combined approach of virtual screening and molecular dynamics (MDs) simulations. Phytoconstituents from the IMPPAT 2.0 database underwent virtual screening to identify potential inhibitors of ALK1. The compounds were initially filtered based on physicochemical parameters, following Lipinski's rules and the PAINS filter. Subsequently, compounds demonstrating high binding affinities in docking analysis were further analyzed. Additional assessments, including ADMET, PAINS, and PASS evaluations, were conducted to identify more potent hits. Through interaction analysis, a phytoconstituent, Candidine, exhibited appreciable affinity and specific interactions with the ALK1 active site. To validate the results, MD simulations and principal components analysis were performed. The MD simulations demonstrated that Candidine stabilized the ALK1 structure and reduced conformational fluctuations. In conclusion, Candidine shows promising potential as binding partners of ALK1. These findings provide a foundation for further exploration and development of Candidine as a lead molecule for therapeutic interventions targeting ALK1‐associated diseases. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a major cause of death in developing countries because of high tobacco consumption. RAC-alpha serine-threonine kinase (AKT1) is considered as an attractive drug target because its prolonged activation and overexpression are associated with cancer progression and metastasis. In addition, several AKT1 inhibitors are being developed to control OSCC and other associated forms of cancers. We performed a screening of the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database to discover promising AKT1 inhibitors which pass through various important filters such as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, physicochemical properties, PAINS (pan-assay interference compounds) filters, PASS (prediction of activity spectra for substances) analysis, and specific interactions with AKT1. Molecules bearing admirable binding affinity and specificity towards AKT1 were selected for further analysis. Initially, we identified 30 natural compounds bearing appreciable affinity and specific interaction with AKT1. Finally, tuberosin and villosol were selected as potent and selective AKT1 inhibitors. To obtain deeper insights into binding mechanism and selectivity, we performed an all-atom molecular dynamics (MD) simulation and principal component analysis (PCA). We observed that both tuberosin and villosol strongly bind to AKT1, and their complexes were stable throughout the simulation trajectories. Our in-depth structure analysis suggested that tuberosin and villosol could be further exploited in the therapeutic targeting of OSCC and other cancers after further clinical validations. [ABSTRACT FROM AUTHOR]

Natural products, medicinal plants, and phytoconstituents serve as important sources and accelerators for anticancer drug discovery, especially when they are combined with virtual screening and molecular simulations against molecular drug targets. Proto-oncogene serine/threonine-protein kinase Pim1 (PIM1) is involved in cell survival and proliferation, with great relevance for oncogenesis. PIM1 plays a major role in the progression of various common complex human cancers, including prostate cancer, acute myeloid leukemia, and other hematopoietic malignancies. The overexpression of PIM1 leads to cancer progression, and thus it is considered as a potential target for drug design and development purposes. Here, we report original in silico findings by employing structure-based virtual screening to discover potential phytoconstituents from the medicinal plants-based compounds, which could inhibit the PIM1 activity, using the IMPPAT (a curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics) database. The initial hits were selected based on their binding affinity toward PIM1 calculated through the molecular docking approach. Subsequently, interaction analyses and molecular dynamics (MD) simulation for 100 ns was carried out to study the conformational dynamics and complex stability of PIM1 with the identified compounds. Importantly, we found that PIM1 forms stable protein–ligand complexes with the phytoconstituents Dehydrotectol and Nordracorubin in particular. Our findings suggest that identified phytoconstituents Dehydrotectol and Nordracorubin bind to PIM1 in ATP-competitive binding mode. These findings and the compounds reported herein warrant further exploration as promising scaffolds for anticancer drug design, discovery, and development. [ABSTRACT FROM AUTHOR]

Exploring protein–ligand interactions is a subject of immense interest, as it provides deeper insights into molecular recognition, mechanism of interaction and subsequent functions. Predicting an accurate model for a protein–ligand interaction is a challenging task. Molecular docking is a computational method used for predicting the preferred orientation, binding conformations and the binding affinity of a ligand to a macromolecular target, especially protein. It has been applied in 'virtual high-throughput screening' of chemical libraries containing millions of compounds to find potential leads in drug design and discovery. Here, we have developed InstaDock, a free and open access Graphical User Interface (GUI) program that performs molecular docking and high-throughput virtual screening efficiently. InstaDock is a single-click GUI that uses QuickVina-W, a modified version of AutoDock Vina for docking calculations, made especially for the convenience of non-bioinformaticians and for people who are not experts in using computers. InstaDock facilitates onboard analysis of docking and visual results in just a single click. To sum up, InstaDock is the easiest and more interactive interface than ever existing GUIs for molecular docking and high-throughput virtual screening. InstaDock is freely available for academic and industrial research purposes via https://hassanlab.org/instadock. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (Mpro or 3CLpro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the Mpro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 Mpro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 Mpro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 Mpro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of Mpro with ZINC02123811. MD simulation results indicated that Mpro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 Mpro to address COVID-19. [ABSTRACT FROM AUTHOR]

Interleukin-2-inducible T-cell kinase (ITK) is a critical tyrosine kinase enzyme that is involved in the activation and differentiation of T cells. ITK is mainly found in T cells, which plays an essential role in controlling T-cell receptor signaling and downstream pathways. ITK regulates the synthesis of cytokines, particularly interleukin-2 (IL-2), and the development of Th2 cells. ITK is of interest for drug discovery and molecular targeting in immunology, autoimmune diseases, and cancer. Here, we report a structure-based virtual screening utilizing a collection of small molecules obtained from the PubChem database with an eye on the discovery of drugs targeting ITK. The compounds were selected according to compliance with the Lipinski's rule of five. The molecular docking investigation focused on prioritizing binding affinity and specific interaction toward the kinase domain. The highest-ranking search results were subjected to identification of possible pan-assay interference compounds (PAINS), assessment of pharmacokinetic properties, and estimation of pharmacological activity using Prediction of Activity Spectra of Substances (PASS) analysis. The interactions among these chemicals and the salient residues in the interleukin-2-inducible T-cell kinase (ITK) kinase domain were unpacked using a two-dimensional approach. The reference inhibitor ITK-Inhibitor-2 (IMM) and four elucidated compounds with PubChem CIDs, namely, 90442621 (PFB), 141764004 (FTP), 149213796 (FPP), and 145983307 (MBD), showed significant binding affinity of −8, −10.4, −9.8, −10.2, and −10.7 kcal/mol, respectively, and high selectivity for the ITK binding pocket. In conclusion, this study reports on the potential of several compounds for therapeutic targeting of ITK. Furthermore, structural analysis revealed the interaction of proposed compounds and active site residues within the ATP-binding pocket is highly similar to known inhibitors but shares distinct interaction patterns that could improve specificity. This specificity and optimization hold potential for the development of next-generation ITK inhibitors with possible applications in the treatment of immune-related disorders and cancers. Further in vitro, in vivo, and translational clinical research are called for. [ABSTRACT FROM AUTHOR]

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski's rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α. [ABSTRACT FROM AUTHOR]

• The main protease (Mpro, 3CLpro) of SARS-CoV-2 is considered as a potential drug target for drug development. • Using advanced computational studies, we have identified two potent inhibitors of SARS-CoV-2 main protease. • Both 6-Deaminosinefungin and UNII-O9H5KY11SV bind strongly to the residues active site pocket. • The complexes of both compounds with the main protease were stable throughout the MD simulation. • Both the molecules may be further exploited as preclinical leads for therapeutic management of COVID-19. Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by a newly emerged highly pathogenic virus called novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Targeting the main protease (Mpro, 3CLpro) of SARS-CoV-2 is an appealing approach for drug development because this enzyme plays a significant role in the viral replication and transcription. The available crystal structures of SARS-CoV-2 Mpro determined in the presence of different ligands and inhibitor-like compounds provide a platform for the quick development of selective inhibitors of SARS-CoV-2 Mpro. In this study, we utilized the structural information of co-crystallized SARS-CoV-2 Mpro for the structure-guided drug discovery of high-affinity inhibitors from the PubChem database. The screened compounds were selected on the basis of their physicochemical properties, drug-likeliness, and strength of affinity to the SARS-CoV-2 Mpro. Finally, we have identified 6-Deaminosinefungin (PubChem ID: 10428963) and UNII-O9H5KY11SV (PubChem ID: 71481120) as potential inhibitors of SARS-CoV-2 Mpro which may be further exploited in drug development to address SARS-CoV-2 pathogenesis. Both compounds are structural analogs of known antivirals, having considerable protease inhibitory potential with improved pharmacological properties. All-atom molecular dynamics simulations suggested SARS-CoV-2 Mpro in complex with these compounds is stable during the simulation period with minimal structural changes. This work provides enough evidence for further implementation of the identified compounds in the development of effective therapeutics of COVID-19. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase molecular target with broad importance for drug discovery, especially in the field of cancer therapeutics. ALK belongs to the insulin receptor superfamily that is involved in various malignancies, including non-small cell lung cancer, anaplastic large cell lymphoma, and neuroblastoma. ALK has been shown to play a role in cancer progression and metastasis, making it one of the prime targets to develop novel anticancer therapeutics. In this context, natural compounds can be an important resource to unravel novel ALK inhibitors. In this study, we report a structure-based virtual screening of natural compounds from the ZINC database, with an eye to potential inhibitors of ALK. Molecular docking was performed on a natural compound library, and top hits holding good binding affinity, docking score, and specificity toward ALK were selected. The hits were further evaluated based on the PAINS (pan-assay interference compounds) filter, ADMET (absorption, distribution, metabolism, excretion, toxicity) properties, PASS (prediction of activity spectra for substances) analysis, and two-dimensional interaction of protein–ligand complexes. Importantly, two natural compounds (ZINC03845566 and ZINC03999625) were identified as potential candidates for ALK, having appreciable affinity and specificity toward the ALK binding pocket and depicting drug-like properties as predicted from ADMET analysis and their physicochemical parameters. An all-atom molecular dynamics simulation for 100 ns on ALK promised stable ALK-ligand complexes. Hence, we conclude that ZINC03845566 and ZINC03999625 can act as potential ALK inhibitors against cancers where ALK plays a role, for example, in lung cancer, among others. All in all, these findings inform future discovery and translational research for ALK inhibitors as anticancer drugs. [ABSTRACT FROM AUTHOR]

Protein kinases are key targets for cancer therapies, with the c-Met receptor tyrosine kinase (MET) and its ligand, hepatocyte growth factor, playing a role in various cancers, including non-small cell lung cancer, gastric cancer, and hepatocellular carcinoma. Although small-molecule inhibitors have been designed to target MET, the development of drug resistance remains a significant challenge to advancing therapeutic strategies. In this study, we employed virtual screening of plant-based compounds sourced from the IMPPAT 2.0 databank to identify potent inhibitors of MET. Preliminary filtering based on the physicochemical parameters following Lipinski's rule of five and pan-assay interference compounds criteria were applied to prioritize hits. Subsequent molecular docking, pharmacokinetic evaluation, prediction of activity spectra for biologically active substances, and specificity assessments facilitated the identification of two promising phytochemicals, neogitogenin and samogenin. Both phytochemicals exhibited considerable drug-like properties with notable binding affinity and selectivity toward MET. Molecular dynamics simulation studies showed the conformational stability of MET with neogitogenin and samogenin. Taken together, these findings suggest that neogitogenin and samogenin hold potential as lead molecules for the development of MET-targeted therapeutics. We call for further evaluations of these phytochemicals in preclinical and experimental studies for anticancer drug discovery and development. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase II (CAII) is one of the zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide, leading to the formation of bicarbonate and proton. CAII plays a significant role in health and disease. For example, CAII helps to maintain eye pressure while regulating the pH of the tumor microenvironment, and by extension, contributing to cancer progression. Owing to its remarkable role in cancer, visual health, and other human diseases, CAII can serve as an attractive therapeutic target. We report an original study based on high-throughput virtual screening of natural compounds from the ZINC database in search of potential inhibitors of CAII. We selected the hits based on the physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, pan-assay interference compound (PAINS) patterns, and interaction analysis. Importantly, two natural compounds were identified, ZINC08918123 and ZINC00952700, bearing considerable affinity and specific interactions to the residues of the CAII-binding pocket with well-organized conformational fitting compatibility. We investigated the conformational dynamics of CAII in complex with the identified compounds through molecular dynamics simulation, which revealed the formation of a stable complex preserved throughout the 100 ns trajectories. The stability of the protein/ligand complexes is maintained by significant numbers of noncovalent interactions throughout the simulations. In conclusion, natural compounds identified in the present study specifically and computer-assisted drug design broadly offer a reliable resource and strategy to discover potential promising therapeutic inhibitors of CAII to cure various cancers and glaucoma after further experimental validation and clinical studies. [ABSTRACT FROM AUTHOR]

Death-associated protein kinase 3 (DAPK3) is a serine/threonine protein kinase that regulates apoptosis, autophagy, transcription, and actin cytoskeleton reorganization. DAPK3 induces morphological alterations in apoptosis when overexpressed, and it is considered a potential drug target in antihypertensive and anticancer drug development. In this article, we report new findings from a structure-guided virtual screening for discovery of phytochemicals that could modulate the elevated expression of DAPK3, and with an eye to anticancer drug discovery. We used the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), a curated database, as part of the methodology. The potential initial hits were identified based on their physicochemical properties and binding affinity toward DAPK3. Subsequently, various filters for drug likeness followed by interaction analysis and molecular dynamics (MD) simulations for 100 nsec were performed to explore the conformational sampling and stability of DAPK3 with the candidate molecules. Notably, the data from all-atom MD simulations and principal component analysis suggested that DAPK3 forms stable complexes with ketanserin and rotenone. In conclusion, this study supports the idea that ketanserin and rotenone bind to DAPK3, and show stability, which can be further explored as promising scaffolds in drug development and therapeutics innovation in clinical contexts such as hypertension and various types of cancer. [ABSTRACT FROM AUTHOR]