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Molecular docking and structure-based drug design strategies.

ABSTRACT: Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.

SUBMITTER: Ferreira LG

PROVIDER: S-EPMC6332083 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Molecular docking and structure-based drug design strategies.

Ferreira Leonardo G LG Dos Santos Ricardo N RN Oliva Glaucius G Andricopulo Adriano D AD

Molecules (Basel, Switzerland) 20150722 7

Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. Thi ...[more]

PMID: 26205061

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Project description:BackgroundThe alarming increase in tick-borne pathogens such as human Babesia microti is an existential threat to global public health. It is a protozoan parasitic infection transmitted by numerous species of the genus Babesia. Second, monkeypox has recently emerged as a public health crisis, and the virus has spread around the world in the post-COVID-19 period with a very rapid transmission rate. These two novel pathogens are a new concern for human health globally and have become a significant obstacle to the development of modern medicine and the economy of the whole world. Currently, there are no approved drugs for the treatment of this disease. So, this research gap encourages us to find a potential inhibitor from a natural source.Methods and materialsIn this study, a series of natural plant-based biomolecules were subjected to in-depth computational investigation to find the most potent inhibitors targeting major pathogenic proteins responsible for the diseases caused by these two pathogens.ResultsAmong them, most of the selected natural compounds are predicted to bind tightly to the targeted proteins that are crucial for the replication of these novel pathogens. Moreover, all the molecules have outstanding ADMET properties such as high aqueous solubility, a higher human gastrointestinal absorption rate, and a lack of any carcinogenic or hepatotoxic effects; most of them followed Lipinski's rule. Finally, the stability of the compounds was determined by molecular dynamics simulations (MDs) for 100 ns. During MDs, we observed that the mentioned compounds have exceptional stability against selected pathogens.ConclusionThese advanced computational strategies reported that 11 lead compounds, including dieckol and amentoflavone, exhibited high potency, excellent drug-like properties, and no toxicity. These compounds demonstrated strong binding affinities to the target enzymes, especially dieckol, which displayed superior stability during molecular dynamics simulations. The MM/PBSA method confirmed the favorable binding energies of amentoflavone and dieckol. However, further in vitro and in vivo studies are necessary to validate their efficacy. Our research highlights the role of Dieckol and Amentoflavone as promising candidates for inhibiting both monkeypox and Babesia microti, demonstrating their multifaceted roles in the control of these pathogens.

Project description:The present work envisaged an adherent luliconazole-loaded bilayer nail lacquer (BNL) with significant transungual activity. The locally applied sustained-release BNL formulation was designed for an improved retention, payload, and final dermatokinetic disposition. A primary step in the fabrication of a BNL included overcoming of physical barriers like α-keratin (also α-keratin), a protein present in human nails, and then allowing the drug molecule to permeate at the site of action. Although luliconazole is an established antifungal agent, has limited clinical exploitation for its use in treating onychomycosis. An in silico study elucidating its interaction with lanosterol-14-α demethylase, an enzyme which is the key region of drug action mechanism, was highly supportive of its imminent clinical potential. Optimization of prepared BNL formulations via response surface modeling (Box-Behnken Design-Expert 10.0.6) logically ascertained the effect of selected independent variables and showcased its effect via dependent responses. Surface morphology of the prepared BNL films was well corroborated for the presence of two distinct polymeric layers through scanning electron microscopy imaging. Nail permeation studies revealed a cumulative drug release of 71.25 ± 0.11% through bovine hooves up to 24 h. Luliconazole while exposing antifungal activity against clinical isolates of Trichophyton rubrum in agar cup-plate method disclosed a 38 mm diameter zone of inhibition. Further, the optimized BNL exhibited a bioadhesive force of 1.9 ± 0.11 N, which assured its retention on the nail surface for prolonged duration of time. In Conclusion, it is deduced that the conventional treatment modalities for onychomycosis require circumvention of certain pharmacotechnical caveats. Therefore, in the present study, a multipronged BNL system was proposed, which negates the need of frequent drug application, improvises cosmetic appearance, yields fruitful therapeutic outcomes, and has a clinical supremacy over the available therapeutics.

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Molecular docking and structure-based drug design strategies.

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Molecular docking and structure-based drug design strategies.

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