{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:14:48Z","timestamp":1783476888999,"version":"3.55.0"},"reference-count":70,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["APVV-21-0108"],"award-info":[{"award-number":["APVV-21-0108"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["PP-COVID-20-0010"],"award-info":[{"award-number":["PP-COVID-20-0010"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["313011T438"],"award-info":[{"award-number":["313011T438"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National infrastructure to support technology transfer in Slovakia\u2014NITT SK II","award":["APVV-21-0108"],"award-info":[{"award-number":["APVV-21-0108"]}]},{"name":"National infrastructure to support technology transfer in Slovakia\u2014NITT SK II","award":["PP-COVID-20-0010"],"award-info":[{"award-number":["PP-COVID-20-0010"]}]},{"name":"National infrastructure to support technology transfer in Slovakia\u2014NITT SK II","award":["313011T438"],"award-info":[{"award-number":["313011T438"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum (PfENR) using computer-aided combinatorial and pharmacophore-based molecular design. The Molecular Mechanics Poisson\u2013Boltzmann Surface Area (MM-PBSA) complexation QSAR model was developed for triclosan-based inhibitors (TCL) and a significant correlation was established between the calculated relative Gibbs free energies of complex formation (\u2206\u2206Gcom) between PfENR and TCL and the observed inhibitory potencies of the enzyme (IC50exp) for a training set of 20 known TCL analogues. Validation of the predictive power of the MM-PBSA QSAR model was carried out with the generation of 3D QSAR pharmacophore (PH4). We obtained a reasonable correlation between the relative Gibbs free energy of complex formation \u2206\u2206Gcom and IC50exp values, which explained approximately 95% of the PfENR inhibition data: pIC50exp=\u22120.0544\u00d7\u2206\u2206Gcom+6.9336,R2=0.95. A similar agreement was established for the PH4 pharmacophore model of the PfENR inhibition (pIC50exp=0.9754\u00d7pIC50pre+0.1596, R2=0.98). Analysis of enzyme\u2013inhibitor binding site interactions suggested suitable building blocks to be used in a virtual combinatorial library of 33,480 TCL analogues. Structural information derived from the complexation model and the PH4 pharmacophore guided us through in silico screening of the virtual combinatorial library of TCL analogues to finally identify potential new TCL inhibitors effective at low nanomolar concentrations. Virtual screening of the library by PfENR-PH4 led to a predicted IC50pre value for the best inhibitor candidate as low as 1.9 nM. Finally, the stability of PfENR-TCLx complexes and the flexibility of the active conformation of the inhibitor for selected top-ranking TCL analogues were checked with the help of molecular dynamics. This computational study resulted in a set of proposed new potent inhibitors with predicted antimalarial effects and favourable pharmacokinetic profiles that act on a novel pharmacological target, PfENR.<\/jats:p>","DOI":"10.3390\/ijms24086916","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:49:29Z","timestamp":1681098569000},"page":"6916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Structure-Based Design and Pharmacophore-Based Virtual Screening of Combinatorial Library of Triclosan Analogues Active against Enoyl-Acyl Carrier Protein Reductase of Plasmodium falciparum with Favourable ADME Profiles"],"prefix":"10.3390","volume":"24","author":[{"given":"Cecile","family":"Bieri","sequence":"first","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), Abidjan 02, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akori","family":"Esmel","sequence":"additional","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), Abidjan 02, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melalie","family":"Keita","sequence":"additional","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), Abidjan 02, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc Calvin Owono","family":"Owono","sequence":"additional","affiliation":[{"name":"Department of Physics, Ecole Normale Sup\u00e9rieure, University of Yaound\u00e9 I, P.O. Box 47, Yaound\u00e9 1, Cameroon"},{"name":"International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Dali","sequence":"additional","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), Abidjan 02, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-5277","authenticated-orcid":false,"given":"Eugene","family":"Megnassan","sequence":"additional","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), Abidjan 02, C\u00f4te d\u2019Ivoire"},{"name":"International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia"},{"name":"International Centre for Theoretical Physics, Strada Costiera 11, I-34151 Trieste, Italy"},{"name":"Laboratoire de Cristallographie\u2014Physique Mol\u00e9culaire, Universit\u00e9 De Cocody, Abidjan 22, C\u00f4te d\u2019Ivoire"},{"name":"Laboratoire de Chimie Organique Structurale et Th\u00e9orique, Universit\u00e9 De Cocody, Abidjan 22, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislav","family":"Miertus","sequence":"additional","affiliation":[{"name":"International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia"},{"name":"Department of Biotechnologies, Faculty of Natural Sciences, University of SS. Cyril and Methodius, SK-91701 Trnava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9378-5860","authenticated-orcid":false,"given":"Vladimir","family":"Frecer","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University Bratislava, SK-83232 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"ref_1","unstructured":"(2023, March 11). World Malaria Report 2021. World Health Organization. Geneva. 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