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Pharmaceuticals
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In Silico and In Vitro Screening of Small Molecule Inhibitors
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In Silico and In Vitro Screening of Small Molecule Inhibitors

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 10 June 2025 | Viewed by 5881

Special Issue Editors

Dr. Usama Ammar

E-Mail Website
Guest Editor
School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, 9 Sighthill Court, Edinburgh EH11 4BN, UK
Interests: isosteric drug design; design of small molecular kinase inhibitors (SMKIs); synthetic medicinal and pharmaceutical chemistry; anticancer drug discovery; melanoma; in silico molecular modeling; early drug discovery
Special Issues, Collections and Topics in MDPI journals
Dr. Domiziana Masci

E-Mail Website
Guest Editor
Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
Interests: medicinal chemistry; drug design and synthesis; small molecules; heterocyclic compounds; hit-to-lead development; anticancer drug discovery; carbonic anhydrase inhibitors; antimicrobial drugs; structure–activity relationship study; molecular docking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the early drug discovery process, the combination of in silico tools with experimental in vitro assays shows unparalleled prospects for accelerating the discovery and identification of potential small molecule inhibitors (SMIs). SMIs are considered promising candidates in targeted therapy and modern drug discovery in different diseases and disorders, including cancers, microbial infections, autoimmune diseases and other metabolic conditions.

This Special Issue aims to highlight the latest advances, challenges and applications of in silico tools and in vitro screening in the field of drug discovery of SMIs. We welcome the submission of research and review articles on advances in the drug discovery, design and development of biological target inhibitors against different disease models. Scientists from both academia and industry are invited to submit their manuscripts covering relevant topics, including the design and synthesis of novel chemical entities (NCEs), repurposing of approved drugs, cell-based or animal experiments and in silico computational approaches to elucidate future directions in drug discovery.

The main objective of this Special Issue is to provide a comprehensive overview of cutting-edge in silico and in vitro screening methodologies for the design and development of bioactive NCEs with therapeutic relevance across various disease contexts, with a specific focus on the elucidation of SMI–biological target interaction mechanisms by employing the synergistic strategy of combining computational with experimental approaches.

Dr. Usama Ammar
Dr. Domiziana Masci
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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • early drug discovery
  • small molecule inhibitors (SMIs)
  • new chemical entities (NCEs)
  • drug repurposing
  • in silico screening
  • in vitro assays
  • targeted therapy
  • high-throughput screening
  • pharmacophore-based modeling
  • bioactive compounds
  • structure-based drug design

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Published Papers (4 papers)

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Research

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17 pages, 3929 KiB  
Article
Exploring Zinc C295 as a Dual HIV-1 Integrase Inhibitor: From Strand Transfer to 3′-Processing Suppression
by Sharif Karim Sayyed, Marzuqa Quraishi, D. S. Prabakaran, Balaji Chandrasekaran, Thiyagarajan Ramesh, Satish Kumar Rajasekharan, Chaitany Jayprakash Raorane, Tareeka Sonawane and Vinothkannan Ravichandran
Pharmaceuticals 2025, 18(1), 30; https://doi.org/10.3390/ph18010030 - 29 Dec 2024
Viewed by 799
Abstract
Background: The global AIDS pandemic highlights the urgent need for novel antiretroviral therapies (ART). In our previous work, Zinc C295 was identified as a potent HIV-1 integrase strand transfer (ST) inhibitor. This study explores its potential to also inhibit 3′-processing (3′P), thereby [...] Read more.
Background: The global AIDS pandemic highlights the urgent need for novel antiretroviral therapies (ART). In our previous work, Zinc C295 was identified as a potent HIV-1 integrase strand transfer (ST) inhibitor. This study explores its potential to also inhibit 3′-processing (3′P), thereby establishing its dual-targeting capability. Methods: The inhibitory activity of Zinc C295 against 3′P was evaluated using a modified in vitro assay adapted from our earlier ST inhibition studies. Molecular docking and molecular dynamics simulations were employed to analyse Zinc C295’s interactions with the 3′P allosteric site of HIV-1 integrase. Results: Zinc C295 demonstrated significant inhibition of HIV-1 integrase 3′P activity in in vitro assays (IC50 = 4.709 ± 0.97 µM). Computational analyses revealed key interactions of Zinc C295 within the enzyme’s allosteric site, providing insights into its dual inhibitory mechanism. Conclusions: Zinc C295’s dual inhibition of HIV-1 integrase ST and 3′P establishes it as a promising candidate for next-generation ART. Its dual-action mechanism may offer potential advantages in enhancing treatment efficacy and addressing drug resistance. Further studies are warranted to evaluate its therapeutic potential in clinical settings. Full article
(This article belongs to the Special Issue In Silico and In Vitro Screening of Small Molecule Inhibitors)
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25 pages, 3059 KiB  
Article
Discovery of Benzopyrone-Based Candidates as Potential Antimicrobial and Photochemotherapeutic Agents through Inhibition of DNA Gyrase Enzyme B: Design, Synthesis, In Vitro and In Silico Evaluation
by Akram Abd El-Haleem, Usama Ammar, Domiziana Masci, Sohair El-Ansary, Doaa Abdel Rahman, Fatma Abou-Elazm and Nehad El-Dydamony
Pharmaceuticals 2024, 17(9), 1197; https://doi.org/10.3390/ph17091197 - 11 Sep 2024
Viewed by 1081
Abstract
Bacterial DNA gyrase is considered one of the validated targets for antibacterial drug discovery. Benzopyrones have been reported as promising derivatives that inhibit bacterial DNA gyrase B through competitive binding into the ATP binding site of the B subunit. In this study, we [...] Read more.
Bacterial DNA gyrase is considered one of the validated targets for antibacterial drug discovery. Benzopyrones have been reported as promising derivatives that inhibit bacterial DNA gyrase B through competitive binding into the ATP binding site of the B subunit. In this study, we designed and synthesized twenty-two benzopyrone-based derivatives with different chemical features to assess their antimicrobial and photosensitizing activities. The antimicrobial activity was evaluated against B. subtilis, S. aureus, E. coli, and C. albicans. Compounds 6a and 6b (rigid tetracyclic-based derivatives), 7a-7f (flexible-linker containing benzopyrones), and 8a-8f (rigid tricyclic-based compounds) exhibited promising results against B. subtilis, S. aureus, and E. coli strains. Additionally, these compounds demonstrated photosensitizing activities against the B. subtilis strain. Both in silico molecular docking and in vitro DNA gyrase supercoiling inhibitory assays were performed to study their potential mechanisms of action. Compounds 8a-8f exhibited the most favorable binding interactions, engaging with key regions within the ATP binding site of the DNA gyrase B domain. Moreover, compound 8d displayed the most potent IC50 value (0.76 μM) compared to reference compounds (novobiocin = 0.41 μM and ciprofloxacin = 2.72 μM). These results establish a foundation for structure-based optimization targeting DNA gyrase inhibition with antibacterial activity. Full article
(This article belongs to the Special Issue In Silico and In Vitro Screening of Small Molecule Inhibitors)
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22 pages, 5532 KiB  
Article
In Silico and In Vivo Studies of β-Sitosterol Nanoparticles as a Potential Therapy for Isoprenaline-Induced Cognitive Impairment in Myocardial Infarction, Targeting Myeloperoxidase
by Partha Saradhi Tallapalli, Yennam Dastagiri Reddy, Deepak A. Yaraguppi, Surya Prabha Matangi, Ranadheer Reddy Challa, Bhaskar Vallamkonda, Sheikh F. Ahmad, Haneen A. Al-Mazroua, Mithun Rudrapal, Prasanth Dintakurthi Sree Naga Bala Krishna and Praveen Kumar Pasala
Pharmaceuticals 2024, 17(8), 1093; https://doi.org/10.3390/ph17081093 - 21 Aug 2024
Viewed by 1820
Abstract
Objective: This study aimed to compare the effects of β-sitosterol nanoparticles (BETNs) and β-sitosterol (BET) on cognitive impairment, oxidative stress, and inflammation in a myocardial infarction (MI) rat model using in silico and in vivo methods. Methods: β-Sitosterol (BET) and myeloperoxidase (MPO) ligand-receptor [...] Read more.
Objective: This study aimed to compare the effects of β-sitosterol nanoparticles (BETNs) and β-sitosterol (BET) on cognitive impairment, oxidative stress, and inflammation in a myocardial infarction (MI) rat model using in silico and in vivo methods. Methods: β-Sitosterol (BET) and myeloperoxidase (MPO) ligand-receptor binding affinities were evaluated using Autodock Vina for docking and Gromacs for dynamics simulations. BET nanoparticles, prepared via solvent evaporation, had their size confirmed by a nanoparticle analyzer. ISO-induced cognitive impairment in rats was assessed through Morris water maze and Cook’s pole climbing tests. Oxidative stress, inflammation, and cardiac injury were evaluated by measuring GSH, SOD, MDA, MPO, CkMB, LDH, lipid profiles, and ECGs. Histopathology of the CA1 hippocampus and myocardial tissue was performed using H&E staining. Results: In silico analyses revealed strong binding affinities between BET and MPO, suggesting BET’s potential anti-inflammatory effect. BETN (119.6 ± 42.6 nm; PDI: 0.809) significantly improved MI-induced cognitive dysfunction in rats (p < 0.001 ***), increased hippocampal GSH (p < 0.01 **) and SOD (p < 0.01 **) levels, and decreased hippocampal MDA (p < 0.05 *) and MPO levels (p < 0.01 **). BETNs also elevated cardiac GSH (p < 0.01 **) and SOD (p < 0.01 **) levels and reduced cardiac MPO (p < 0.01 **), CkMB (p < 0.001 **) and LDH (p < 0.001 **) levels. It restored lipid profiles, normalized ECG patterns, and improved histology in the hippocampal CA1 region and myocardium. Conclusions: Compared with BET treatment, BETNs were more effective in improving cognitive impairment, oxidative damage, and inflammation in MI rats, suggesting its potential in treating cognitive dysfunction and associated pathological changes in MI. Full article
(This article belongs to the Special Issue In Silico and In Vitro Screening of Small Molecule Inhibitors)
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Review

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20 pages, 2223 KiB  
Review
Small Molecules in Parkinson’s Disease Therapy: From Dopamine Pathways to New Emerging Targets
by Hwayoung Lee, Ahmed Elkamhawy, Polina Rakhalskaya, Qili Lu, Hossam Nada, Guofeng Quan and Kyeong Lee
Pharmaceuticals 2024, 17(12), 1688; https://doi.org/10.3390/ph17121688 - 14 Dec 2024
Viewed by 1363
Abstract
Parkinson’s disease (PD) is a chronic, progressive neurological disorder affecting approximately 10 million people worldwide, with prevalence expected to rise as the global population ages. It is characterized by the degeneration of dopamine-producing neurons in the substantia nigra pars compacta, leading to motor [...] Read more.
Parkinson’s disease (PD) is a chronic, progressive neurological disorder affecting approximately 10 million people worldwide, with prevalence expected to rise as the global population ages. It is characterized by the degeneration of dopamine-producing neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremor, rigidity, bradykinesia, postural instability, and gait disturbances, as well as non-motor symptoms including olfactory disturbances, sleep disorders, and depression. Currently, no cure exists for PD, and most available therapies focus on symptom alleviation. This dopamine deficiency impairs motor control, and since dopamine itself cannot cross the blood–brain barrier (BBB), the precursor L-Dopa is commonly used in treatment. L-Dopa is administered with enzyme inhibitors to prevent premature conversion outside the brain, allowing it to cross the BBB and convert to dopamine within the central nervous system. Although these therapies have improved symptom management, recent research has revealed additional molecular factors in PD pathology, such as α-synuclein aggregation, mitochondrial dysfunction, and lysosomal abnormalities, contributing to its complexity. These discoveries open up possibilities for neuroprotective therapies that could slow disease progression. In this review, we categorize PD therapeutic targets into two main groups: currently used therapies and targets under active research. We also introduce promising small-molecule compounds studied between 2019 and 2023, which may represent future treatment options. By examining both established and emerging targets, we aim to highlight effective strategies and potential directions for future drug development in Parkinson’s disease therapy. Full article
(This article belongs to the Special Issue In Silico and In Vitro Screening of Small Molecule Inhibitors)
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