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New Insights into Biomolecular Structures and Interactions

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 12273

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Special Issue Editors

Dr. Pankaj Pandey

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Guest Editor

National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
Interests: computational medicinal chemistry; cheminformatics; cannabinoid and opioid receptors; GPCR; docking; quantum chemistry; molecular dynamics; homology modeling; virtual screening; QSAR

Dr. Robert J. Doerksen

E-Mail Website
Guest Editor

Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
Interests: computational medicinal chemistry; cannabinoid receptors; drug discovery; quantum chemistry; allosteric modulators; protein modeling; quantitative structure–activity relationships
Special Issues, Collections and Topics in MDPI journals

Dr. Babu L. Tekwani

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Guest Editor

Division of Drug Discovery, Southern Research 2000 9th Avenue South, Birmingham, AL 35205, USA
Interests: tropical parasitic diseases; malaria and leishmaniasis; infectious diseases; drug discovery; neuropharmacology

Special Issue Information

Dear Colleagues,

Previously, only limited computational studies could be performed on the biomolecular structures and interactions that are relevant to many fields of science. However, now, the vast modern computational resources available allow calculations and simulations to tackle scientific questions involving biological processes with sufficient accuracy and at appropriate time scales to uncover details of the structures, interactions, and functions of a wide array of biomolecules at a molecular level. Researchers may now utilize these tools to envisage and determine the physicochemical and pharmacokinetic properties of new drugs, allowing for the improved prediction of the interactions between ligands and their molecular targets versus traditional animal toxicological studies. For example, recent developments allow traditional protein–ligand interaction prediction methods to be combined with limited experimental information and highly scalable molecular dynamics (MD) simulation methods to more accurately predict the thermodynamics and kinetics associated with drug–target recognition and binding mechanisms. Advancements in predictive modeling have now made structure-based drug design streamlined for future synthesis and testing against therapeutic targets. In addition, quantum chemical calculations combined with experimental NMR and electronic circular dichroism (ECD) enable researchers to firmly establish the absolute configuration of complex natural products.

This Special Issue will focus on contemporary computational approaches to answer key questions about the structural and functional dynamics of protein–ligand complexes, structural characterization of complex natural product scaffolds, and prediction of therapeutic targets with the goal of permitting and enhancing comparisons to experimental data to solve important problems. Within this broad context, this Special Issue of Molecules welcomes original research and review articles focusing on the biomolecular structures and interactions combining both in silico and experimental approaches.

Dr. Pankaj Pandey
Dr. Robert J. Doerksen
Dr. Babu L. Tekwani
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

biomolecular structures and interactions
drug–target recognition
thermodynamics and kinetics properties
absolute configurations
natural products
computational medicinal chemistry
protein modeling
docking
quantum chemistry
molecular modeling
molecular dynamics
virtual screening
QSAR
in vitro/vivo

Published Papers (5 papers)

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Research

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15 pages, 3130 KiB

Open AccessArticle

Site-Selective Incorporation of a Functional Group into Lys175 in the Vicinity of the Active Site of Chymotrypsin by Using Peptidyl α-Aminoalkylphosphonate Diphenyl Ester-Derivatives

by Shin Ono, Masato Koga, Yuya Arimura, Takahiro Hatakeyama, Mai Kobayashi, Jun-ichi Sagara, Takahiko Nakai, Yoshikazu Horino, Hirofumi Kuroda, Hiroshi Oyama and Kazunari Arima

Molecules 2023, 28(7), 3150; https://doi.org/10.3390/molecules28073150 - 31 Mar 2023

Viewed by 1040

Abstract

We previously reported that Lys175 in the region of the active site of chymotrypsin (Csin) could be site-selectively modified by using an N-hydroxy succinimide (NHS) ester of the peptidyl derivative containing 1-amino-2-ethylphenylphosphonate diphenyl ester [NHS-Suc-Ala-Ala-Phe^P(OPh)₂]. In this study, the Lys175-selective modification method was expanded to incorporate functional groups into Lys 175 in Csin. Two types of peptidyl phosphonate derivatives with the dansyl group (Dan) as a functional molecule, Dan-β-Ala-[Asp(NHS) or Glu(NHS)]-Ala-Ala-(R)-Phe^P(OPh)₂ (DanD and DanE, respectively), were synthesized, and their action was evaluated when modifying Lys175 in Csin. Ion-exchange chromatography (IEC), fluorescence spectroscopy, and LC-MS/MS were used to analyze the products from the reaction of Csin with DanD or DanE. By IEC and LC-MS/MS, the results showed that DanE reacted with Csin more effectively than DanD to produce the modified Csin (DanMCsin) bearing Dan at Lys175. DanMCsin exhibited an enzymatic activity corresponding to 1/120 of Csin against Suc-Ala-Ala-Phe-pNA. In addition, an effect of Lys175 modification on the access of the proteinaceous Bowman–Birk inhibitor to the active site of DanMCsin was investigated. In conclusion, by using a peptidyl derivative containing 1-amino-2-ethylphenylphosphonate diphenyl ester, we demonstrated that a functional group could be incorporated into Lys175 in Csin. Full article

(This article belongs to the Special Issue New Insights into Biomolecular Structures and Interactions)

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15 pages, 3583 KiB

Open AccessFeature PaperArticle

In Vitro and In Silico Studies of Neolignans from Magnolia grandiflora L. Seeds against Human Cannabinoids and Opioid Receptors

by Pankaj Pandey, Mallika Kumarihamy, Krishna Chaturvedi, Mohamed A. M. Ibrahim, Janet A. Lambert, Murrell Godfrey, Robert J. Doerksen and Ilias Muhammad

Molecules 2023, 28(3), 1253; https://doi.org/10.3390/molecules28031253 - 27 Jan 2023

Cited by 2 | Viewed by 2286

Abstract

Magnolia grandiflora L. (Magnoliaceae) is a plant of considerable medicinal significance; its flowers and seeds have been used in various traditional remedies. Radioligand binding assays of n-hexane seeds extract showed displacement of radioligand for cannabinoid (CB1 and CB2) and opioid δ (delta), κ (kappa), and µ (mu) receptors. Bioactivity-guided fractionation afforded 4-O-methylhonokiol (1), magnolol (2), and honokiol (3), which showed higher binding to cannabinoid rather than opioid receptors in radioligand binding assays. Compounds 1–3, together with the dihydro analog of 2 (4), displayed selective affinity towards CB2R (K_i values of 0.29, 1.4, 1.94, and 0.99 μM, respectively), compared to CB1R (K_i 3.85, 17.82, 14.55, and 19.08 μM, respectively). An equal mixture of 2 and 3 (1:1 ratio) showed additive displacement activity towards the tested receptors compared to either 2 or 3 alone, which in turn provides an explanation for the strong displacement activity of the n-hexane extract. Due to the unavailability of an NMR or X-ray crystal structure of bound neolignans with the CB1 and CB2 receptors, a docking study was performed to predict ligand–protein interactions at a molecular level and to delineate structure-activity relationships (SAR) of the neolignan analogs with the CB1 and CB2 receptors. The putative binding modes of neolignans 1–3 and previously reported related analogs (4, 4a, 5, 5a, 6, 6a, and 6b) into the active site of the CB1 and CB2 receptors were assessed for the first time via molecular docking and binding free-energy (∆G) calculations. The docking and ∆G results revealed the importance of a hydroxyl moiety in the molecules that forms strong H-bonding with Ser383 and Ser285 within CB1R and CB2R, respectively. The impact of a shift from a hydroxyl to the methoxy group on experimental binding affinity to CB1R versus CB2R was explained through ∆G data and the orientation of the alkyl chain within the CB1R. This comprehensive SAR, influenced by the computational study and the observed in vitro displacement binding affinities, has indicated the potential of magnolia neolignans for developing new CB agonists for potential use as analgesics, anti-inflammatory agents, or anxiolytics. Full article

(This article belongs to the Special Issue New Insights into Biomolecular Structures and Interactions)

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16 pages, 3994 KiB

Open AccessArticle

Collagen Type II—Chitosan Interactions as Dependent on Hydroxylation and Acetylation Inferred from Molecular Dynamics Simulations

by Maciej Przybyłek, Piotr Bełdowski, Florian Wieland, Piotr Cysewski and Alina Sionkowska

Molecules 2023, 28(1), 154; https://doi.org/10.3390/molecules28010154 - 24 Dec 2022

Cited by 3 | Viewed by 1818

Abstract

Chitosan–collagen blends have been widely applied in tissue engineering, joints diseases treatment, and many other biomedical fields. Understanding the affinity between chitosan and collagen type II is particularly relevant in the context of mechanical properties modulation, which is closely associated with designing biomaterials suitable for cartilage and synovial fluid regeneration. However, many structural features influence chitosan’s affinity for collagen. One of the most important ones is the deacetylation degree (DD) in chitosan and the hydroxylation degree (HD) of proline (PRO) moieties in collagen. In this paper, combinations of both factors were analyzed using a very efficient molecular dynamics approach. It was found that DD and HD modifications significantly affect the structural features of the complex related to considered types of interactions, namely hydrogen bonds, hydrophobic, and ionic contacts. In the case of hydrogen bonds both direct and indirect (water bridges) contacts were examined. In case of the most collagen analogues, a very good correlation between binding free energy and DD was observed. Full article

(This article belongs to the Special Issue New Insights into Biomolecular Structures and Interactions)

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15 pages, 2156 KiB

Open AccessArticle

Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study

by Vasudevan Mani, Minhajul Arfeen, Syed Imam Rabbani, Ali Shariq and Palanisamy Amirthalingam

Molecules 2022, 27(21), 7364; https://doi.org/10.3390/molecules27217364 - 29 Oct 2022

Cited by 8 | Viewed by 1788

Abstract

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The ‘nootropic-like’ activity could be related to diminished AChE and neuroinflammatory mediator levels. Full article

(This article belongs to the Special Issue New Insights into Biomolecular Structures and Interactions)

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Review

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14 pages, 2276 KiB

Open AccessReview

Griseofulvin: An Updated Overview of Old and Current Knowledge

by Parisa Aris, Yulong Wei, Masoud Mohamadzadeh and Xuhua Xia

Molecules 2022, 27(20), 7034; https://doi.org/10.3390/molecules27207034 - 18 Oct 2022

Cited by 16 | Viewed by 4161

Abstract

Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from −3.34 to −5.61 kcal mol⁻¹. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human. Full article

(This article belongs to the Special Issue New Insights into Biomolecular Structures and Interactions)

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