Identifying Inhibitor-SARS-CoV2-3CLpro Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations

Molecules, Год журнала: 2025, Номер 30(4), С. 805 - 805

Опубликована: Фев. 10, 2025

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in virus's life cycle and plays a pivotal role COVID-19. Understanding how small molecules inhibit 3CLpro's activity vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance sampling 3CLpro conformations conducted correlation network analysis (CNA) explore interactions between different structural domains. Our findings indicate that CNA-identified node domain II acts conduit, transferring conformational changes from catalytic regions domains I II, triggered by binding inhibitors (7YY, 7XB, Y6G), III, thereby modulating activity. Normal mode (NMA) principal component (PCA) revealed inhibitor affects flexibility collective movements sites influencing function. free energies, predicted both MM-GBSA QM/MM-GBSA methods, showed high with experimental data, validating reliability our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, E166, identified through residue-based energy decomposition, present promising targets design drugs could facilitate development clinically effective inhibitors.

Язык: Английский

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Binding Mechanism of Inhibitors to BRD4 and BRD9 Decoded by Multiple Independent Molecular Dynamics Simulations and Deep Learning

Molecules, Год журнала: 2024, Номер 29(8), С. 1857 - 1857

Опубликована: Апрель 19, 2024

Bromodomain 4 and 9 (BRD4 BRD9) have been regarded as important targets of drug designs in regard to the treatment multiple diseases. In our current study, molecular dynamics (MD) simulations, deep learning (DL) binding free energy calculations are integrated probe modes three inhibitors (H1B, JQ1 TVU) BRD4 BRD9. The MD trajectory-based DL successfully identify significant functional function domains, such BC-loop ZA-loop. information from post-processing analysis simulations indicates that inhibitor highly influences structural flexibility dynamic behavior results MM-GBSA not only suggest ability H1B, TVU BRD9 stronger than BRD4, but they also verify van der Walls interactions primary forces responsible for binding. hot spots revealed by residue-based estimation provide target sites design This work is anticipated useful theoretical aids development selective over BRD family members.

Язык: Английский

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Computational Elucidation of a Monobody Targeting the Phosphatase Domain of SHP2

Biomolecules, Год журнала: 2025, Номер 15(2), С. 217 - 217

Опубликована: Фев. 2, 2025

Src homology 2 (SH2) domain-containing phosphatase (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated various pathological conditions, including cancers and developmental disorders. Despite importance, the molecular basis of SHP2’s regulatory mechanism remains poorly understood, hindering development effective targeted therapies. In this study, we utilized high-specificity monobody Mb11 to investigate interaction with SHP2 domain (PTP) using multiple replica dynamics simulations. Our analyses elucidate precise mechanisms through which achieves selective recognition stabilization SHP2-PTP domain, identifying residues networks essential for high binding specificity dynamics. Furthermore, study highlights pivotal role residue C459 preserving structural integrity functional coherence complex, acting as central node within network underpinning stability efficiency. These findings have significantly advanced understanding underlying involvement disease-related pathology while simultaneously paving way rational design inhibitors, offering significant implications therapeutic strategies SHP2-associated diseases contributing broader scope precision medicine.

Язык: Английский

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Probing the role of zinc ion in metallo-β-lactamase inhibitor binding by using multiple molecular dynamics simulations

Results in Chemistry, Год журнала: 2025, Номер 15, С. 102171 - 102171

Опубликована: Март 6, 2025

Язык: Английский

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AlloReverse: multiscale understanding among hierarchical allosteric regulations

Nucleic Acids Research, Год журнала: 2023, Номер 51(W1), С. W33 - W38

Опубликована: Апрель 18, 2023

Abstract Increasing data in allostery are requiring analysis of coupling relationships among different allosteric sites on a single protein. Here, based our previous efforts reversed communication theory, we have developed AlloReverse, web server for multiscale multiple regulations. AlloReverse integrates protein dynamics and machine learning to discover residues, regulation pathways. Especially, could reveal hierarchical between pathways couplings sites, offering whole map allostery. The shows good performance re-emerging known Moreover, applied explore global CDC42 SIRT3. predicted novel residues both systems, the functionality was validated experimentally. It also suggests possible scheme combined therapy or bivalent drugs Taken together, is workflow providing complete believed aid target identification, drug design understanding biological mechanisms. freely available all users at https://mdl.shsmu.edu.cn/AlloReverse/ http://www.allostery.net/AlloReverse/.

Язык: Английский

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Unveiling the State Transition Mechanisms of Ras Proteins through Enhanced Sampling and QM/MM Simulations

The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(6), С. 1418 - 1427

Опубликована: Фев. 7, 2024

In cells, wild-type RasGTP complexes exist in two distinct states: active State 2 and inactive 1. These regulate their functions by transitioning between the states. However, mechanisms underlying this state transition have not been clearly elucidated. To address this, we conducted a detailed simulation study to characterize energetics of stable states involved transitions HRasGTP complex, specifically from This was achieved employing multiscale quantum mechanics/molecular mechanics enhanced sampling molecular dynamics methods. Based on results, constructed two-dimensional free energy landscapes that provide crucial information about conformational changes complex Furthermore, also explored intermediate product during guanosine triphosphate hydrolysis. HRas serves as valuable reference for understanding corresponding events both KRas NRas well.

Язык: Английский

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Predicting Conformational Ensembles of Intrinsically Disordered Proteins: From Molecular Dynamics to Machine Learning

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(32), С. 8177 - 8186

Опубликована: Авг. 2, 2024

Intrinsically disordered proteins and regions (IDP/IDRs) are ubiquitous across all domains of life. Characterized by a lack stable tertiary structure, IDP/IDRs populate diverse set transiently formed structural states that can promiscuously adapt upon binding with specific interaction partners and/or certain alterations in environmental conditions. This malleability is foundational for their role as tunable hubs core cellular processes such signaling, transcription, translation. Tracing the conformational ensemble an IDP/IDR its perturbation response to regulatory cues thus paramount illuminating function. However, heterogeneity poses several challenges. Here, we review experimental computational methods devised disentangle landscape IDP/IDRs, highlighting recent advances permit proteome-wide scans conformations. We briefly evaluate selected using N-terminal human copper transporter 1 test case outline further challenges prediction.

Язык: Английский

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Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins

Expert Opinion on Drug Discovery, Год журнала: 2024, Номер 19(10), С. 1259 - 1279

Опубликована: Авг. 6, 2024

Molecular Dynamics (MD) simulations can support mechanism-based drug design. Indeed, MD by capturing biomolecule motions at finite temperatures reveal hidden binding sites, accurately predict drug-binding poses, and estimate the thermodynamics kinetics, crucial information for discovery campaigns. Small-Guanosine Triphosphate Phosphohydrolases (GTPases) regulate a cascade of signaling events, that affect most cellular processes. Their deregulation is linked to several diseases, making them appealing targets. The broad roles small-GTPases in processes recent approval covalent KRas inhibitor as an anticancer agent renewed interest targeting small-GTPase with small molecules.

Язык: Английский

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Single cell spatial biology over developmental time can decipher pediatric brain pathologies

Neurobiology of Disease, Год журнала: 2024, Номер 199, С. 106597 - 106597

Опубликована: Июль 9, 2024

Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, networks. They also germline mutations an impaired prenatal differentiation origin. may differ in the timing of events proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to cell states, which depend on spatial location, gene expression during development. These attributes are crucial as develops sequentially, single-cell organization influences state, thus function. Our underlying premise is root cause pediatric differentiation. Data related tumors, disorders, (sub)types, locations, developing scant. However, emerging single technologies, including transcriptomic, biology, high-resolution imaging performed over developmental time, could be transformational deciphering pathologies thereby pharmacology.

Язык: Английский

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Structural and energetic insights into the selective inhibition of PKMYT1 against WEE1

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 42(6), С. 3010 - 3018

Опубликована: Июнь 22, 2023

Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family and responsible for regulation CDK1 phosphorylation, has been considered promising therapeutic target cancer therapy. However, highly structural conservation ATP-binding sites poses challenge to design selective inhibitors PKMYT1. Here, molecular docking, multiple microsecond-length dynamics (MD) simulations end-point free energy calculations were performed uncover mechanism binding selectivity RP-6306 toward PKMYT1 over its homologous kinase WEE1. The specificity reported in previous experimental bioassays was clarified by MD calculations. Further, prediction indicated that largely derived from difference protein-ligand electrostatic interactions. per-residue decomposition suggested non-conserved gatekeeper residue hinge domain PKMYT1/WEE1, Thr187/Asn376, is critical factor In addition, water-mediated hydrogen bond formed between Gly191 at PKMYT1/RP-6306 complex, which absent WEE1/RP-6306 complex. This study expected offer useful information more potent inhibitors.Communicated Ramaswamy H. Sarma

Язык: Английский

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