Research

19 pages, 5468 KiB

Open AccessArticle

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors

by Maksym Platonov, Oleksandr Maximyuk, Alexey Rayevsky, Vasyl Hurmach, Olena Iegorova, Vasyl Naumchyk, Elijah Bulgakov, Andrii Cherninskyi, Danil Ozheredov, Serhiy V. Ryabukhin, Oleg Krishtal and Dmytro M. Volochnyuk

Int. J. Mol. Sci. 2024, 25(7), 3584; https://doi.org/10.3390/ijms25073584 - 22 Mar 2024

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Abstract

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key [...] Read more.

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1–ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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14 pages, 3409 KiB

Open AccessArticle

Molecular Modeling of the Multiple-Substrate Activity of the Human Recombinant Intra-Melanosomal Domain of Tyrosinase and Its OCA1B-Related Mutant Variant P406L

by Monika B. Dolinska and Yuri V. Sergeev

Int. J. Mol. Sci. 2024, 25(6), 3373; https://doi.org/10.3390/ijms25063373 - 16 Mar 2024

Viewed by 422

Abstract

Tyrosinase serves as the key enzyme in melanin biosynthesis, catalyzing the initial steps of the pathway, the hydroxylation of the amino acid L-tyrosine into L-3,4-dihydroxyphenylalanine (L-DOPA), followed by the subsequent oxidation of L-DOPA into dopaquinone (DQ), and it facilitates the conversion of 5,6-dihydroxyindole-2-carboxylic [...] Read more.

Tyrosinase serves as the key enzyme in melanin biosynthesis, catalyzing the initial steps of the pathway, the hydroxylation of the amino acid L-tyrosine into L-3,4-dihydroxyphenylalanine (L-DOPA), followed by the subsequent oxidation of L-DOPA into dopaquinone (DQ), and it facilitates the conversion of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into 5,6-indolequinone-2-carboxylic acid (IQCA) and 5,6-dihydroxy indole (DHI) into indolequinone (IQ). Despite its versatile substrate capabilities, the precise mechanism underlying tyrosinase’s multi-substrate activity remains unclear. Previously, we expressed, purified, and characterized the recombinant intra-melanosomal domain of human tyrosinase (rTyr). Here, we demonstrate that rTyr mimics native human tyrosinase’s catalytic activities in vitro and in silico. Molecular docking and molecular dynamics (MD) simulations, based on rTyr’s homology model, reveal variable durability and binding preferences among tyrosinase substrates and products. Analysis of root mean square deviation (RMSD) highlights the significance of conserved residues (E203, K334, F347, and V377), which exhibit flexibility during the ligands’ binding. Additionally, in silico analysis demonstrated that the OCA1B-related P406L mutation in tyrosinase substantially influences substrate binding, as evidenced by the decreased number of stable ligand conformations. This correlation underscores the mutation’s impact on substrate docking, which aligns with the observed reduction in rTyr activity. Our study highlights how rTyr dynamically adjusts its structure to accommodate diverse substrates and suggests a way to modulate rTyr ligand plasticity. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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18 pages, 5884 KiB

Open AccessArticle

Computational Modeling of the Interactions between DPP IV and Hemorphins

by Priya Antony, Bincy Baby, Amie Jobe and Ranjit Vijayan

Int. J. Mol. Sci. 2024, 25(5), 3059; https://doi.org/10.3390/ijms25053059 - 06 Mar 2024

Viewed by 580

Abstract

Type 2 diabetes is a chronic metabolic disorder characterized by high blood glucose levels due to either insufficient insulin production or ineffective utilization of insulin by the body. The enzyme dipeptidyl peptidase IV (DPP IV) plays a crucial role in degrading incretins that [...] Read more.

Type 2 diabetes is a chronic metabolic disorder characterized by high blood glucose levels due to either insufficient insulin production or ineffective utilization of insulin by the body. The enzyme dipeptidyl peptidase IV (DPP IV) plays a crucial role in degrading incretins that stimulate insulin secretion. Therefore, the inhibition of DPP IV is an established approach for the treatment of diabetes. Hemorphins are a class of short endogenous bioactive peptides produced by the enzymatic degradation of hemoglobin chains. Numerous in vitro and in vivo physiological effects of hemorphins, including DPP IV inhibiting activity, have been documented in different systems and tissues. However, the underlying molecular binding behavior of these peptides with DPP IV remains unknown. Here, computational approaches such as protein–peptide molecular docking and extensive molecular dynamics (MD) simulations were employed to identify the binding pose and stability of peptides in the active site of DPP IV. Findings indicate that hemorphins lacking the hydrophobic residues LVV and VV at the N terminal region strongly bind to the conserved residues in the active site of DPP IV. Furthermore, interactions with these critical residues were sustained throughout the duration of multiple 500 ns MD simulations. Notably, hemorphin 7 showed higher binding affinity and sustained interactions by binding to S1 and S2 pockets of DPP IV. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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15 pages, 7928 KiB

Open AccessArticle

GTP-Bound N-Ras Conformational States and Substates Are Modulated by Membrane and Point Mutation

by Alexandra Farcas and Lorant Janosi

Int. J. Mol. Sci. 2024, 25(3), 1430; https://doi.org/10.3390/ijms25031430 - 24 Jan 2024

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Abstract

Oncogenic Ras proteins are known to present multiple conformational states, as reported by the great variety of crystallographic structures. The GTP-bound states are grouped into two main states: the “inactive” state 1 and the “active” state 2. Recent reports on H-Ras have shown [...] Read more.

Oncogenic Ras proteins are known to present multiple conformational states, as reported by the great variety of crystallographic structures. The GTP-bound states are grouped into two main states: the “inactive” state 1 and the “active” state 2. Recent reports on H-Ras have shown that state 2 exhibits two substates, directly related to the orientation of Tyr32: toward the GTP-bound pocket and outwards. In this paper, we show that N-Ras exhibits another substate of state 2, related to a third orientation of Tyr32, toward Ala18 and parallel to the GTP-bound pocket. We also show that this substate is highly sampled in the G12V mutation of N-Ras and barely present in its wild-type form, and that the G12V mutation prohibits the sampling of the GTPase-activating protein (GAP) binding substate, rendering this mutation oncogenic. Furthermore, using molecular dynamics simulations, we explore the importance of the membrane on N-Ras’ conformational state dynamics and its strong influence on Ras protein stability. Moreover, the membrane has a significant influence on the conformational (sub)states sampling of Ras. This, in turn, is of crucial importance in the activation/deactivation cycle of Ras, due to the binding of guanine nucleotide exchange factor proteins (GEFs)/GTPase-activating proteins (GAPs). Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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14 pages, 5003 KiB

Open AccessArticle

Computational Design of Novel Griseofulvin Derivatives Demonstrating Potential Antibacterial Activity: Insights from Molecular Docking and Molecular Dynamics Simulation

by Parisa Aris, Masoud Mohamadzadeh, Maaroof Zarei and Xuhua Xia

Int. J. Mol. Sci. 2024, 25(2), 1039; https://doi.org/10.3390/ijms25021039 - 15 Jan 2024

Cited by 1 | Viewed by 854

Abstract

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with [...] Read more.

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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19 pages, 4648 KiB

Open AccessArticle

Unveiling the Anti-Cancer Potential of Onoceranoid Triterpenes from Lansium domesticum Corr. cv. kokosan: An In Silico Study against Estrogen Receptor Alpha

by Ari Hardianto, Sarah Syifa Mardetia, Wanda Destiarani, Yudha Prawira Budiman, Dikdik Kurnia and Tri Mayanti

Int. J. Mol. Sci. 2023, 24(19), 15033; https://doi.org/10.3390/ijms241915033 - 09 Oct 2023

Cited by 1 | Viewed by 1136

Abstract

Breast cancer is a significant global concern, with tamoxifen, the standard treatment, raising long-term safety issues due to side effects. In this study, we evaluated the potential of five onoceranoid triterpenes from Lansium domesticum Corr. cv. kokosan against estrogen receptor alpha (ERα) using [...] Read more.

Breast cancer is a significant global concern, with tamoxifen, the standard treatment, raising long-term safety issues due to side effects. In this study, we evaluated the potential of five onoceranoid triterpenes from Lansium domesticum Corr. cv. kokosan against estrogen receptor alpha (ERα) using in silico techniques. Utilizing molecular docking, Lipinski’s rule of five, in silico ADMET, and molecular dynamics simulations, we assessed the potency of five onoceranoid triterpenes against ERα. Molecular docking indicated competitive binding energies for these triterpenes relative to the active form of tamoxifen (4OHT) and estradiol, an ERα native ligand. Three triterpenes met drug-likeness criteria with favorable ADMET profiles. Notably, 2 demonstrated superior binding affinity in molecular dynamics simulations, outperforming estradiol, closely followed by 3 and 4. Hierarchical clustering on principal components (HCPC) and the spatial distribution of contact surface area (CSA) analyses suggest that these triterpenes, especially 2, may act as antagonist ligands akin to 4OHT. These findings highlight the potential of onoceranoid triterpenes in treating ERα-related breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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33 pages, 7764 KiB

Open AccessArticle

Interaction of Synthetic Cannabinoid Receptor Agonists with Cannabinoid Receptor I: Insights into Activation Molecular Mechanism

by Sergei Gavryushov, Anton Bashilov, Konstantin V. Cherashev-Tumanov, Nikolay N. Kuzmich, Tatyana I. Burykina and Boris N. Izotov

Int. J. Mol. Sci. 2023, 24(19), 14874; https://doi.org/10.3390/ijms241914874 - 03 Oct 2023

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Abstract

Synthetic cannabinoid receptor agonists (SCRAs) have become a wide group of new psychoactive substances since the 2010s. For the last few years, the X-ray structures of the complexes of cannabinoid receptor I (CB₁) with SCRAs as well as the complexes of [...] Read more.

Synthetic cannabinoid receptor agonists (SCRAs) have become a wide group of new psychoactive substances since the 2010s. For the last few years, the X-ray structures of the complexes of cannabinoid receptor I (CB₁) with SCRAs as well as the complexes of CB₁ with its antagonist have been published. Based on those data, SCRA–CB₁ interactions are analyzed in detail, using molecular modeling and molecular dynamics simulations. The molecular mechanism of the conformational transformation of the transmembrane domain of CB₁ caused by its interaction with SCRA is studied. These conformational changes allosterically modulate the CB₁–G_i complex, providing activation of the G_i protein. Based on the X-ray-determined structures of the CB₁–ligand complexes, a stable apo conformation of inactive CB₁ with a relatively low potential barrier of receptor activation was modeled. For that model, molecular dynamic simulations of SCRA binding to CB₁ led to the active state of CB₁, which allowed us to explore the key features of this activation and the molecular mechanism of the receptor’s structural transformation. The simulated CB₁ activation is in accordance with the previously published experimental data for the activation at protein mutations or structural changes of ligands. The key feature of the suggested activation mechanism is the determination of the stiff core of the CB₁ transmembrane domain and the statement that the entire conformational transformation of the receptor to the active state is caused by a shift of alpha helix TM7 relative to this core. The shift itself is caused by protein–ligand interactions. It was verified via steered molecular dynamics simulations of the X-ray-determined structures of the inactive receptor, which resulted in the active conformation of CB₁ irrespective of the placement of agonist ligand in the receptor’s active site. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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17 pages, 8880 KiB

Open AccessArticle

Molecular Mechanism of Mutational Disruption of DCLK1 Autoinhibition Provides a Rationale for Inhibitor Screening

by Weizhi Chen, Rui Liu, Yamei Yu, Dongqing Wei, Qiang Chen and Qin Xu

Int. J. Mol. Sci. 2023, 24(18), 14020; https://doi.org/10.3390/ijms241814020 - 13 Sep 2023

Viewed by 920

Abstract

Doublecortin-like kinase 1 (DCLK1) is a prominent kinase involved in carcinogenesis, serving as a diagnostic marker for early cancer detection and prevention, as well as a target for cancer therapy. Extensive research efforts have been dedicated to understanding its role in cancer development [...] Read more.

Doublecortin-like kinase 1 (DCLK1) is a prominent kinase involved in carcinogenesis, serving as a diagnostic marker for early cancer detection and prevention, as well as a target for cancer therapy. Extensive research efforts have been dedicated to understanding its role in cancer development and designing selective inhibitors. In our previous work, we successfully determined the crystal structure of DCLK1 while it was bound to its autoinhibitory domain (AID) at the active site. By analyzing this structure, we were able to uncover the intricate molecular mechanisms behind specific cancer-causing mutations in DCLK1. Utilizing molecular dynamics simulations, we discovered that these mutations disrupt the smooth assembly of the AID, particularly affecting the R2 helix, into the kinase domain (KD). This disruption leads to the exposure of the D533 residue of the DFG (Asp-Phe-Gly) motif in the KD, either through steric hindrance, the rearrangement of electrostatic interactions, or the disruption of local structures in the AID. With these molecular insights, we conducted a screening process to identify potential small-molecule inhibitors that could bind to DCLK1 through an alternative binding mode. To assess the binding affinity of these inhibitors to the KD of DCLK1, we performed calculations on their binding energy and conducted SPR experiments. We anticipate that our study will contribute novel perspectives to the field of drug screening and optimization, particularly in targeting DCLK1. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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