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Computational and Experimental Approaches for Discovery and Development of New Products

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 1695

Special Issue Editor

Environmental Health Sciences (EHS), University of Michigan, Ann Arbor, MI 48109, USA
Interests: computational molecular modeling with applications to drug discovery; mechanisms of neurodegenerative diseases; neurotoxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Computational and advanced experimental methods have become indispensable for the discovery and development of new products, such as pharmaceutical agents, agricultural chemicals, disinfectants, and exotic materials.

Computational tools include ligand-based and structure-based approaches, combinations of the two, and varying degrees of augmentation with quantum mechanics (QM), molecular mechanics (MM), and molecular dynamics (MD).

Ligand-based screening directs its focus toward intrinsic properties of small molecules and how to use these characteristics to predict compounds with a desired biological activity. Structure-based screening examines interactions of ligands with macromolecular targets to understand and predict the biological effect of interest.

Advanced experimental techniques include high-throughput technologies such as robotic systems to enable rapid acquisition of laboratory data and its computational analysis using modern omics methodologies.

Together, in silico and automated laboratory techniques make it possible to assess the potential of extremely large numbers of compounds at greatly reduced cost and much higher speed than would be possible with traditional wet lab procedures.

Nevertheless, the accuracy of computational approaches remains in need of improvement. To address the accuracy issue, recent advances in theory, software, and hardware appear to hold great promise. In particular, the emerging fields of artificial intelligence (AI) and machine learning (ML) are being applied to virtual screening with good effect. At the same time, commercial and open-source molecular modeling software continue to improve and to be increasingly accessible with respect to cost and ease of use. Similarly, ongoing advances in hardware, including CPUs and GPUs, are enabling compute-intensive processes such as molecular dynamics (MD) simulations to be carried out routinely on desktop workstations or on a larger scale using supercomputers or cloud-based high-performance clusters.

The goal of this Special Issue is to bring together a collection of high-quality research and review articles highlighting diverse facets of computational and/or advanced experimental approaches with applications in the discovery and development of new products.

Prof. Dr. Rudy J. Richardson
Guest Editor

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

  • virtual screening
  • computational molecular modeling
  • ligand-based screening
  • structure-based screening
  • high-throughput experimental/laboratory screening
  • artificial intelligence (AI)
  • machine learning (ML)
  • computer technology (CPUs, GPUs, connectivity)
  • cheminformatics
  • bioinformatics
  • epigenomics, genomics, metabolomics, proteomics, transcriptomics
  • similarity searching
  • pharmacophore mapping
  • molecular docking
  • ensemble docking
  • inverse docking
  • molecular databases
  • interference with protein–protein interactions
  • proteolysis-targeting chimeras (PROTACs)
  • molecular modeling software
  • small-molecule databases
  • macromolecular target databases
  • alpha fold
  • Protein Data Bank (PDB)
  • cambridge crystallographic data center (CCDC)
  • drug repurposing
  • quantitative structure–activity relationships (QSAR)
  • computational and experimental design of drugs, crop protectants, disinfectants, and exotic materials
  • quantum chemistry (ab initio and semi-empirical) applied to product design

Published Papers (2 papers)

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Research

23 pages, 11598 KiB  
Article
Temperature-Induced Restructuring of Mycolic Acid Bilayers Modeling the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study
Molecules 2024, 29(3), 696; https://doi.org/10.3390/molecules29030696 - 02 Feb 2024
Viewed by 503
Abstract
The emergence of new drug-resistant strains of the tuberculosis pathogen Mycobacterium tuberculosis (Mtb) is a new challenge for modern medicine. Its resistance capacity is closely related to the properties of the outer membrane of the Mtb cell wall, which is a bilayer membrane [...] Read more.
The emergence of new drug-resistant strains of the tuberculosis pathogen Mycobacterium tuberculosis (Mtb) is a new challenge for modern medicine. Its resistance capacity is closely related to the properties of the outer membrane of the Mtb cell wall, which is a bilayer membrane formed by mycolic acids (MAs) and their derivatives. To date, the molecular mechanisms of the response of the Mtb outer membrane to external factors and, in particular, elevated temperatures have not been sufficiently studied. In this work, we consider the temperature-induced changes in the structure, ordering, and molecular mobility of bilayer MA membranes of various chemical and conformational compositions. Using all-atom long-term molecular dynamics simulations of various MA membranes, we report the kinetic parameters of temperature-dependent changes in the MA self-diffusion coefficients and conformational compositions, including the apparent activation energies of these processes, as well as the characteristic times of ordering changes and the features of phase transitions occurring over a wide range of elevated temperatures. Understanding these effects could be useful for the prevention of drug resistance and the development of membrane-targeting pharmaceuticals, as well as in the design of membrane-based materials. Full article
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29 pages, 2952 KiB  
Article
Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer’s Disease
Molecules 2024, 29(2), 321; https://doi.org/10.3390/molecules29020321 - 09 Jan 2024
Viewed by 829
Abstract
Effective therapeutics for Alzheimer’s disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities [...] Read more.
Effective therapeutics for Alzheimer’s disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure–activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited the inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood–brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD. Full article
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