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Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II

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

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 16743

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Prof. Dr. Tanveer A. Wani

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Department of Pharmaceutical Chemistry, King Saud University, Riyadh, Saudi Arabia
Interests: binding interaction; protein-ligand interaction; transport protein; fluorescence quenching; molecular docking; molecular dynamic simulation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Seema Zargar

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Guest Editor

Department of Biochemistry, King Saud University, Riyadh, Saudi Arabia
Interests: cancer; expression profiling; oxidative stress; molecular docking; plasma protein; binding
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Dr. Afzal Hussain

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Guest Editor

Department of Pharmacognosy, King Saud University, Riyadh, Saudi Arabia
Interests: drug development; chromatographic techniques; bioanalytical; novel synthesis of drug
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Biological macromolecules interact with each other or ligands and form complexes with them. Quantification of the binding of chemical entities to a protein is an important early screening step during drug discovery and is of fundamental interest for estimating safety margins during drug development. The investigation of binding parameters has received significant attention since its importance was recognized at the beginning of the 20th century. Spectroscopy has emerged as an invaluable tool for such studies and has proven to be more efficient with improved time and cost-effectiveness. A detailed understanding of the protein–ligand interactions is, therefore, central to understanding biology at the molecular level. Moreover, knowledge of the mechanisms responsible for the protein-ligand recognition and binding will also facilitate the discovery, design, and development of drugs. Current progress in experimental and computational methods for identifying and characterizing ligand binding sites on protein targets provides biological insights and has great significance for drug discoveries.

It is a great pleasure to invite you to contribute to this Special Issue of Molecules, Spectroscopic, Thermodynamic, and Molecular Docking Study on ‎Molecular Mechanism of Drugs that will cover the latest research applications in the field. we aim to collect contributions in the form of original research articles, and Review articles to add new insight into the role of Spectroscopic, Thermodynamic and Molecular Docking Study in drug–protein interactions in biological processes.

Prof. Dr. Tanveer A. Wani
Prof. Dr. Seema Zargar
Dr. Afzal Hussain
Guest Editors

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Keywords

binding interaction
protein-ligand interaction
transport protein
fluorescence quenching
molecular docking
molecular dynamic simulation

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Published Papers (8 papers)

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Research

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22 pages, 11540 KiB

Open AccessArticle

Exploration of Specific Fluoroquinolone Interaction with SARS-CoV-2 Main Protease (Mpro) to Battle COVID-19: DFT, Molecular Docking, ADME and Cardiotoxicity Studies

by Muhammad Asim Khan, Sadaf Mutahir, Muhammad Atif Tariq and Abdulrahman A. Almehizia

Molecules 2024, 29(19), 4721; https://doi.org/10.3390/molecules29194721 - 5 Oct 2024

Viewed by 1500

Abstract

Herein, the pharmacokinetic profiles, binding interactions, and molecular properties of fluoroquinolone derivatives as prospective antiviral drugs are examined using a combination of docking, ADME, and DFT simulations. The effectiveness of the ligands is compared with the clinically tested and FDA-authorized medicine remdesivir. The findings demonstrated encouraging binding energies, indicating possible inhibitory effectiveness against SARS-CoV-2 M^pro. The fluoroquinolone derivatives also exhibit promising ADME characteristics, although compounds 5, 6, 9, 12–20 possess poor values, suggesting that oral administration may be possible. The potential of the selected compounds as SARS-CoV-2 M^pro inhibitors is thoroughly understood because of the integrated analysis of DFT, with compound 11 demonstrating the highest energy gap of 0.2604 eV of, docking with viral targets with docking scores of −7.9 to −5.9 kcal/mol, with compound 18 demonstrating the highest docking score, which is at the 13th position in energy difference in the DFT data. Their favorable electrical properties, robust binding interactions with viral targets, and attractive pharmacokinetic profiles boost their potential as prospective study subjects. These substances have the potential to be transformed into cutting-edge antiviral therapies that specifically target SARS-CoV-2 M^pro and related coronaviruses. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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17 pages, 3189 KiB

Open AccessArticle

pH-Dependent HEWL-AuNPs Interactions: Optical Study

by Elena A. Molkova, Vladimir I. Pustovoy, Evgenia V. Stepanova, Irina V. Gorudko, Maxim E. Astashev, Alexander V. Simakin, Ruslan M. Sarimov and Sergey V. Gudkov

Molecules 2024, 29(1), 82; https://doi.org/10.3390/molecules29010082 - 22 Dec 2023

Cited by 2 | Viewed by 984

Abstract

Optical methods (spectroscopy, spectrofluorometry, dynamic light scattering, and refractometry) were used to study the change in the state of hen egg-white lysozyme (HEWL), protein molecules, and gold nanoparticles (AuNPs) in aqueous colloids with changes in pH, and the interaction of protein molecules with nanoparticles was also studied. It was shown that changing pH may be the easiest way to control the protein corona on gold nanoparticles. In a colloid of nanoparticles, both in the presence and absence of protein, aggregation–deaggregation, and in a protein colloid, monomerization–dimerization–aggregation are the main processes when pH is changed. A specific point at pH 7.5, where a transition of the colloidal system from one state to another is observed, has been found using all the optical methods mentioned. It has been shown that gold nanoparticles can stabilize HEWL protein molecules at alkaline pH while maintaining enzymatic activity, which can be used in practice. The data obtained in this manuscript allow for the state of HEWL colloids and gold nanoparticles to be monitored using one or two simple and accessible optical methods. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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17 pages, 4804 KiB

Open AccessArticle

Bioactivity-Guided Synthesis: In Silico and In Vitro Studies of β-Glucosidase Inhibitors to Cope with Hepatic Cytotoxicity

by Aneela Khushal, Umar Farooq, Sara Khan, Azhar Rasul, Tanveer A. Wani, Seema Zargar, Sohail Anjum Shahzad, Syed Majid Bukhari and Nazeer Ahmad Khan

Molecules 2023, 28(18), 6548; https://doi.org/10.3390/molecules28186548 - 9 Sep 2023

Viewed by 1575

Abstract

The major cause of hyperglycemia can generally be attributed to β-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of β-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (β-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with β-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC₅₀ = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against β-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC₅₀ value (0.048 µM) for 3c is better than the standard (thalidomide: IC₅₀ 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the β-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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22 pages, 5676 KiB

Open AccessArticle

In Silico Investigation of the Molecular Mechanism of PARP1 Inhibition for the Treatment of BRCA-Deficient Cancers

by Fengqin Yan, Zhenfu Fu, Guo Li and Zhiguo Wang

Molecules 2023, 28(4), 1829; https://doi.org/10.3390/molecules28041829 - 15 Feb 2023

Cited by 1 | Viewed by 2230

Abstract

The protein PARP1, which plays a crucial role in DNA repair processes, is an attractive target for cancer therapy, especially for BRCA-deficient cancers. To overcome the acquired drug resistance of PARP1, PARP1 G-quadruplex (G4) identified in the PARP1-promotor region is gaining increasing attention. Aiming to explore the molecular mechanism of PARP1 inhibition with PARP1 G4 and PARP1 as potential targets, a comparative investigation of the binding characteristics of the newly identified G4 stabilizer MTR-106, which showed modest activity against talazoparib-resistant xenograft models and the FDA-approved PARP1 inhibitor (PARPi) talazoparib, were performed through molecular simulations. Combined analyses revealed that, relative to the groove binding of talazoparib, MTR-106 induced the formation of a sandwich framework through stacking with dT₁ and the capping G-pair (dG₂ and dG₁₄) of PARP1 G4 to present largely enhanced binding affinity. For the binding with PARP1, although both were located in the catalytic pocket of PARP1, MTR-106 formed more extensive interactions with the surrounding PARP1 residues compared to talazoparib, in line with its increased binding strength. Importantly, vdW interaction was recognized as a decisive factor in the bindings with PARP1 G4 and PARP1. Collectively, these findings demonstrated the ascendancy of MTR-106 over talazoparib at the atomic level and revealed that the dual targeting of PARP1 G4 and PARP1 might be pivotal for PARPi that is capable of overcoming acquired drug resistance, providing valuable information for the design and development of novel drugs. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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13 pages, 3389 KiB

Open AccessArticle

In Silico Identification of Novel Derivatives of Rifampicin Targeting Ribonuclease VapC2 of M. tuberculosis H37Rv: Rifampicin Derivatives Target VapC2 of Mtb H37Rv

by Satyamvada Maurya, Amita Jain, Md Tabish Rehman, Ali Hakamy, Farkad Bantun, Mohamed F. AlAjmi, Vineeta Singh, Aafreen Zehra, Feroz Khan, Shafiul Haque and Bhartendu Nath Mishra

Molecules 2023, 28(4), 1652; https://doi.org/10.3390/molecules28041652 - 8 Feb 2023

Viewed by 2377

Abstract

The emergence of multi-drug-resistant Mycobacterium tuberculosis (Mtb) strains has rendered many of the currently available anti-TB drugs ineffective. Hence, there is a pressing need to discover new potential drug targets/candidates. In this study, attempts have been made to identify novel inhibitors of the ribonuclease VapC2 of Mtb H37Rv using various computational techniques. Ribonuclease VapC2 Mtb H37Rv’s protein structure was retrieved from the PDB databank, 22 currently used anti-TB drugs were retrieved from the PubChem database, and protein–ligand interactions were analyzed by docking studies. Out of the 22 drugs, rifampicin (RIF), being a first-line drug, showed the best binding energy (−8.8 Kcal/mol) with Mtb H37Rv VapC2; hence, it was selected as a parent molecule for the design of its derivatives. Based on shape score and radial plot criteria, out of 500 derivatives designed through SPARK (Cresset^®, Royston, UK) program, the 10 best RIF derivatives were selected for further studies. All the selected derivatives followed the ADME criteria concerning drug-likeness. The docking of ribonuclease VapC2 with RIF derivatives revealed the best binding energy of −8.1 Kcal/mol with derivative 1 (i.e., RIF-155841). A quantitative structure–activity relationship study revealed that derivative 1’s activity assists in the inhibition of ribonuclease VapC2. The stability of the VapC2–RIF155841 complex was evaluated using molecular dynamics simulations for 50 ns and the complex was found to be stable after 10 nsec. Further, a chemical synthesis scheme was designed for the newly identified RIF derivative (RIF-155841), which verified that its chemical synthesis is possible for future in vitro/in vivo experimental validation. Overall, this study evaluated the potential of the newly designed RIF derivatives with respect to the Mtb VapC2 protein, which is predicted to be involved in some indispensable processes of the related pathogen. Future experimental studies regarding RIF-155841, including the exploration of the remaining RIF derivatives, are warranted to verify our current findings. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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15 pages, 3439 KiB

Open AccessFeature PaperArticle

Elucidating the Role of Santalol as a Potent Inhibitor of Tyrosinase: In Vitro and In Silico Approaches

by Nabeel Ali, Zainy Zehra, Anas Shamsi, Md. Amjad Beg, Zahoor Ahmad Parray, Israil, Md. Ali Imam, Naseem A. Gaur, Md. Imtaiyaz Hassan, Anis Ahmad Chaudhary, Hassan Ahmad Rudayni, Mohammed Ibrahim Alghonaim, Sulaiman A. Alsalamah and Asimul Islam

Molecules 2022, 27(24), 8915; https://doi.org/10.3390/molecules27248915 - 15 Dec 2022

Cited by 3 | Viewed by 1906

Abstract

This research work focuses on the potential application of an organic compound, santalol, obtained from santalum album, in the inhibition of the enzyme tyrosinase, which is actively involved in the biosynthesis of melanin pigment. Over-production of melanin causes undesirable pigmentation in humans as well as other organisms and significantly downgrades their aesthetic value. The study is designed to explain the purification of tyrosinase from the mushroom Agaricus bisporus, followed by activity assays and enzyme kinetics to give insight into the santalol-modulated tyrosinase inhibition in a dose-dependent manner. The multi-spectroscopic techniques such as UV-vis, fluorescence, and isothermal calorimetry are employed to deduce the efficiency of santalol as a potential candidate against tyrosinase enzyme activity. Experimental results are further verified by molecular docking. Santalol, derived from the essential oils of santalum album, has been widely used as a remedy for skin disorders and a potion for a fair complexion since ancient times. Based on enzyme kinetics and biophysical characterization, this is the first scientific evidence where santalol inhibits tyrosinase, and santalol may be employed in the agriculture, food, and cosmetic industries to prevent excess melanin formation or browning. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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14 pages, 2859 KiB

Open AccessArticle

Exploring 2-Tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines Derivatives as Alkaline Phosphatase Inhibitors: Biochemical Evaluation and Computational Analysis

by Aftab Ahmed, Sajid-ur Rehman, Syeda Abida Ejaz, Aamer Saeed, Rabail Ujan, Pervaiz Ali Channar, Khalida Mahar, Reshma Sahito, Sarah M. Albogami, Qamar Abbas, Mohammed Alorabi, Michel De Waard and Gaber El-Saber Batiha

Molecules 2022, 27(19), 6766; https://doi.org/10.3390/molecules27196766 - 10 Oct 2022

Cited by 3 | Viewed by 1826

Abstract

The current study focused on the laboratory approach in conjunction with computational methods for the synthesis and bioactivity assessment of unique 2-tetradecanoylimino-3-aryl-4-methyl-1,3-thiazolines (2a–2k). Processes included cyclizing 1-aroyl-3-arylthioureas with propan-2-one in the presence of trimethylamine and bromine. By using spectroscopic techniques and elemental analyses, structures were elucidated. To assess the electronic properties, density functional theory (DFT) calculations were made, while binding interactions of synthesized derivatives were studied by the molecular docking tool. Promising results were found during the evaluation of bioactivity of synthesized compounds against alkaline phosphatase. The drug likeliness score, an indicator used for any chemical entity posing as a drug, was within acceptable limits. The data suggested that most of the derivatives were potent inhibitors of alkaline phosphatase, which in turn may act as lead molecules to synthesize derivatives having desired pharmacological profiles for the treatment of specific diseases associated with abnormal levels of ALPs. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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Review

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28 pages, 23807 KiB

Open AccessReview

Structure-Based Design of Novel MAO-B Inhibitors: A Review

by Emilio Mateev, Maya Georgieva, Alexandrina Mateeva, Alexander Zlatkov, Shaban Ahmad, Khalid Raza, Vasco Azevedo and Debmalya Barh

Molecules 2023, 28(12), 4814; https://doi.org/10.3390/molecules28124814 - 16 Jun 2023

Cited by 8 | Viewed by 3296

Abstract

With the significant growth of patients suffering from neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase type B (MAO-B) are promptly emerging as distinguished structures for the treatment of the latter. As a promising function of computer-aided drug design (CADD), structure-based virtual screening (SBVS) is being heavily applied in processes of drug discovery and development. The utilization of molecular docking, as a helping tool for SBVS, is providing essential data about the poses and the occurring interactions between ligands and target molecules. The current work presents a brief discussion of the role of MAOs in the treatment of NDs, insight into the advantages and drawbacks of docking simulations and docking software, and a look into the active sites of MAO-A and MAO-B and their main characteristics. Thereafter, we report new chemical classes of MAO-B inhibitors and the essential fragments required for stable interactions focusing mainly on papers published in the last five years. The reviewed cases are separated into several chemically distinct groups. Moreover, a modest table for rapid revision of the revised works including the structures of the reported inhibitors together with the utilized docking software and the PDB codes of the crystal targets applied in each study is provided. Our work could be beneficial for further investigations in the search for novel, effective, and selective MAO-B inhibitors. Full article

(This article belongs to the Special Issue Spectroscopic, Thermodynamic and Molecular Docking Studies on Molecular Mechanisms of Drug Binding to Proteins II)

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