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Special Issue "Application of Computational Methods in Drug Design"

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

Deadline for manuscript submissions: 15 November 2018

Special Issue Editors

Guest Editor
Prof. Rino Ragno

Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Roma, Italy
Website | E-Mail
Interests: design and synthesis of bioactive compounds; development of new 3-D QSAR procedures and their application in drug design; molecular docking in drug design; extraction of bioactive compounds from natural sources
Guest Editor
Prof. Milan Mladenović

Kragujevac Center for Computational Biochemistry, University of Kragujevac, Faculty of Science, Radoja Domanovića 12, 34000 Kragujevac, Republic of Serbia
Website | E-Mail
Interests: design and synthesis of bioactive compounds; development of new 3-D QSAR procedures and their application in drug design; structure-based and ligand-based drug design; in vitro–in vivo assays in drug design

Special Issue Information

Dear Colleagues,

The proposed workshop, entitled “DesignIT-TO-LEAD: 1st Computational Medicinal Chemistry WorkShop” is intended as a first trial to establish regular workshops in drug design on a biennual based frequency. The DesignIT-TO-LEAD will be organized at the Faculty of Science, University of Kragujevac, Republic of Serbia, from from September 3rd to September 8th, 2018.

The contribution of computational methodologies to drug discovery is no longer a matter of dispute, and all major world pharmaceutical and biotechnology companies use computational design tools. Computer-aided drug design encompasses computational methods and resources that are used to facilitate the design and discovery of new bioactive chemical entities.

This workshop “DesignIT-TO-LEAD: 1st Computational Medicinal Chemistry WorkShop” will cover the main computational techniques currently used in the drug discovery process, supplying a basic level of knowledge of this field. All the presented computational approaches will focus mainly on the development of three-dimensional quantitative structure–activity relationships (3-D QSAR) and related tools.

The course will be divided into theoretical lesson and practical sessions with the aim of allowing participants to independently apply the computational techniques to their own projects.

Prof. Rino Ragno
Prof. Milan Mladenović
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 papers will be 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 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 1800 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

  • 3-D QSAR
  • Drug Design
  • Molecular Docking
  • Ligand-based alignment
  • Computational Medicinal Chemistry

Published Papers (3 papers)

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Research

Open AccessFeature PaperArticle The Targeted Pesticides as Acetylcholinesterase Inhibitors: Comprehensive Cross-Organism Molecular Modelling Studies Performed to Anticipate the Pharmacology of Harmfulness to Humans In Vitro
Molecules 2018, 23(9), 2192; https://doi.org/10.3390/molecules23092192
Received: 6 August 2018 / Revised: 24 August 2018 / Accepted: 24 August 2018 / Published: 30 August 2018
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Abstract
Commercially available pesticides were examined as Mus musculus and Homo sapiens acetylcholinesterase (mAChE and hAChE) inhibitors by means of ligand-based (LB) and structure-based (SB) in silico approaches. Initially, the crystal structures of simazine, monocrotophos, dimethoate, and acetamiprid were reproduced using
[...] Read more.
Commercially available pesticides were examined as Mus musculus and Homo sapiens acetylcholinesterase (mAChE and hAChE) inhibitors by means of ligand-based (LB) and structure-based (SB) in silico approaches. Initially, the crystal structures of simazine, monocrotophos, dimethoate, and acetamiprid were reproduced using various force fields. Subsequently, LB alignment rules were assessed and applied to determine the inter synaptic conformations of atrazine, propazine, carbofuran, carbaryl, tebufenozide, imidacloprid, diuron, monuron, and linuron. Afterwards, molecular docking and dynamics SB studies were performed on either mAChE or hAChE, to predict the listed pesticides’ binding modes. Calculated energies of global minima (Eglob_min) and free energies of binding (∆Gbinding) were correlated with the pesticides’ acute toxicities (i.e., the LD50 values) against mice, as well to generate the model that could predict the LD50s against humans. Although for most of the pesticides the low Eglob_min correlates with the high acute toxicity, it is the ∆Gbinding that conditions the LD50 values for all the evaluated pesticides. Derived pLD50 = f(∆Gbinding) mAChE model may predict the pLD50 against hAChE, too. The hAChE inhibition by atrazine, propazine, and simazine (the most toxic pesticides) was elucidated by SB quantum mechanics (QM) DFT mechanistic and concentration-dependent kinetic studies, enriching the knowledge for design of less toxic pesticides. Full article
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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Open AccessArticle Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches
Molecules 2018, 23(7), 1527; https://doi.org/10.3390/molecules23071527
Received: 17 May 2018 / Revised: 15 June 2018 / Accepted: 18 June 2018 / Published: 25 June 2018
PDF Full-text (6113 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed
[...] Read more.
The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r2), leave-one-out (LOO) cross validated correlation coefficient (q2), bootstrapping, and Fisher’s randomization test. The highly reliable and predictive CoMFA (q2 = 0.569, r2 = 0.979) and CoMSIA (q2 = 0.500, r2 = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein’s active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds. Full article
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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Open AccessArticle New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies
Molecules 2018, 23(7), 1506; https://doi.org/10.3390/molecules23071506
Received: 22 May 2018 / Revised: 15 June 2018 / Accepted: 19 June 2018 / Published: 21 June 2018
PDF Full-text (3498 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate
[...] Read more.
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies. Full article
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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Graphical abstract

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