{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T05:02:12Z","timestamp":1774155732971,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Direcci\u00f3n General de C\u00f3mputo y de Tecnolog\u00edas de Informaci\u00f3n y 530 Comunicaci\u00f3n (DGTIC), UNAM","award":["LANCAD-UNAM-DGTIC-335"],"award-info":[{"award-number":["LANCAD-UNAM-DGTIC-335"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available in the supplementary material.<\/jats:p>","DOI":"10.3390\/biom11121805","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T02:40:02Z","timestamp":1638412802000},"page":"1805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products"],"prefix":"10.3390","volume":"11","author":[{"given":"Ana L.","family":"Ch\u00e1vez-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida Universidad 3000, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3283-8284","authenticated-orcid":false,"given":"K. Eur\u00eddice","family":"Ju\u00e1rez-Mercado","sequence":"additional","affiliation":[{"name":"DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida Universidad 3000, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-8662","authenticated-orcid":false,"given":"Fernanda I.","family":"Sald\u00edvar-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida Universidad 3000, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4940-1107","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Medina-Franco","sequence":"additional","affiliation":[{"name":"DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Avenida Universidad 3000, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"ref_1","unstructured":"(2021, July 15). HIV\/AIDS. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hiv-aids."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3389\/fpubh.2017.00032","article-title":"HIV Diagnosis and Treatment through Advanced Technologies","volume":"5","author":"Zulfiqar","year":"2017","journal-title":"Front. Public Health"},{"key":"ref_3","first-page":"95","article-title":"HIV protease inhibitors: A review of molecular selectivity and toxicity","volume":"7","author":"Lv","year":"2015","journal-title":"HIV AIDS"},{"key":"ref_4","unstructured":"(2021, April 28). FDA, Available online: https:\/\/www.fda.gov\/consumers\/free-publications-women\/hiv-and-aids-medicines-help-you."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10792","DOI":"10.1002\/anie.201814681","article-title":"Automated de novo drug design: Are we nearly there yet?","volume":"58","author":"Schneider","year":"2019","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_6","unstructured":"Torjesen, I. (2021, May 29). Drug Development: The Journey of a Medicine from Lab to Shelf. Available online: https:\/\/pharmaceutical-journal.com\/article\/feature\/drug-development-the-journey-of-a-medicine-from-lab-to-shelf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"728551","DOI":"10.3389\/fddsv.2021.728551","article-title":"Grand challenges of computer-aided drug design: The road ahead","volume":"1","year":"2021","journal-title":"Front. Drug Discov."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"575","DOI":"10.4155\/fmc-2020-0262","article-title":"De novo design of new chemical entities for SARS-CoV-2 using artificial intelligence","volume":"13","author":"Bung","year":"2021","journal-title":"Future Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cartwright, H. (2021). Computational approaches for de novo drug design: Past, present, and future. Artificial Neural Networks, Springer.","DOI":"10.1007\/978-1-0716-0826-5"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mouchlis, V.D., Afantitis, A., Serra, A., Fratello, M., Papadiamantis, A.G., Aidinis, V., Lynch, I., Greco, D., and Melagraki, G. (2021). Advances in De Novo Drug Design: From Conventional to Machine Learning Methods. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041676"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1016\/j.drudis.2021.05.019","article-title":"De novo molecular design and generative models","volume":"26","author":"Meyers","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.asoc.2014.09.042","article-title":"Evolutionary algorithms for de novo drug design\u2014A survey","volume":"27","author":"Devi","year":"2015","journal-title":"Appl. Soft Comput."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bajorath, J. (2011). De Novo Drug Design. Chemoinformatics and Computational Chemical Biology, Humana Press.","DOI":"10.1007\/978-1-60761-839-3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nrd.2016.109","article-title":"Twenty years on: The impact of fragments on drug discovery","volume":"15","author":"Erlanson","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1042\/BST20190694","article-title":"Fragments: Where are we now?","volume":"48","author":"Osborne","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107319","DOI":"10.1016\/j.compbiolchem.2020.107319","article-title":"De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study","volume":"88","author":"Shinde","year":"2020","journal-title":"Comput. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s10822-020-00300-6","article-title":"Enhancing reaction-based de novo design using a multi-label reaction class recommender","volume":"34","author":"Ghiandoni","year":"2020","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13321-020-00466-z","article-title":"Chemoinformatics-based enumeration of chemical libraries: A tutorial","volume":"12","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22478","DOI":"10.1021\/acsomega.1c03389","article-title":"Advances in the exploration of the epigenetic televant chemical space","volume":"6","year":"2021","journal-title":"ACS Omega"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1039\/C5NP00121H","article-title":"The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery","volume":"33","author":"Barnes","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2000050","DOI":"10.1002\/minf.202000050","article-title":"A Fragment library of natural products and its comparative chemoinformatic characterization","volume":"39","year":"2020","journal-title":"Mol. Inform."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41557-019-0411-x","article-title":"Principle and design of pseudo-natural products","volume":"12","author":"Karageorgis","year":"2020","journal-title":"Nat. Chem."},{"key":"ref_24","unstructured":"(2021, July 19). ChemDiv. Available online: https:\/\/store.chemdiv.com\/."},{"key":"ref_25","unstructured":"(2021, July 16). Enamine. Available online: https:\/\/enamine.net\/compound-collections\/fragment-collection."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13321-020-00424-9","article-title":"Review on natural products databases: Where to find data in 2020","volume":"12","author":"Sorokina","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1021\/ci00057a005","article-title":"SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules","volume":"28","author":"Weininger","year":"1988","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_28","unstructured":"(2021, May 21). toolkit RDKit. Available online: http:\/\/rdkit.org."},{"key":"ref_29","unstructured":"(2021, May 21). MolVS. Available online: https:\/\/molvs.readthedocs.io\/en\/latest\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular properties that influence the oral bioavailability of drug candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1021\/ci970429i","article-title":"RECAPRetrosynthetic combinatorial analysis procedure: A powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry","volume":"38","author":"Lewell","year":"1998","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"113287","DOI":"10.1016\/j.ejmech.2021.113287","article-title":"Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors","volume":"215","author":"Zhao","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/095632020801900301","article-title":"Bevirimat: A novel maturation inhibitor for the treatment of hiv-1 infection","volume":"19","author":"Martin","year":"2008","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_35","unstructured":"Chackalamannil, S., Rotella, D., and Ward, S.E. (2017). 5.19\u2014New Antiretrovirals for HIV and Antivirals for HBV, Elsevier."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1021\/jm901782m","article-title":"Anti-AIDS Agents 81. Design, synthesis, and structure\u2212activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors","volume":"53","author":"Qian","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s11596-018-1891-4","article-title":"Structure and anti-HIV activity of betulinic acid analogues","volume":"38","author":"Huang","year":"2018","journal-title":"Curr. Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1021\/ci100050t","article-title":"Extended-connectivity fingerprints","volume":"50","author":"Rogers","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1021\/ci010132r","article-title":"Reoptimization of MDL Keys for use in drug discovery","volume":"42","author":"Durant","year":"2002","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13321-020-0416-x","article-title":"Visualization of very large high-dimensional data sets as minimum spanning trees","volume":"12","author":"Probst","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_41","unstructured":"(2021, September 14). TMAP. Available online: https:\/\/tmap.gdb.tools\/."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Greener, J.G., Kandathil, S.M., Moffat, L., and Jones, D.T. (2021). A guide to machine learning for biologists. Nat. Rev. Mol. Cell Biol.","DOI":"10.1038\/s41580-021-00407-0"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.12688\/f1000research.21540.2","article-title":"Functional group and diversity analysis of BIOFACQUIM: A Mexican natural product database","volume":"8","year":"2020","journal-title":"F1000Research"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ch\u00e1vez-Hern\u00e1ndez, A.L., S\u00e1nchez-Cruz, N., and Medina-Franco, J.L. (2020). Fragment library of natural products and compound databases for drug discovery. Biomolecules, 10.","DOI":"10.3390\/biom10111518"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1758-2946-1-8","article-title":"Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions","volume":"1","author":"Ertl","year":"2009","journal-title":"J. Cheminform."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16076","DOI":"10.1021\/acsomega.0c01581","article-title":"In silico ADME\/Tox profiling of natural products: A focus on BIOFACQUIM","volume":"5","year":"2020","journal-title":"ACS Omega"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"115539","DOI":"10.1016\/j.bmc.2020.115539","article-title":"Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy","volume":"28","author":"Lenci","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Laurini, R.B.T.-G.K.I. (2017). 5\u2014Geographic Relations, Elsevier.","DOI":"10.1016\/B978-1-78548-243-4.50005-0"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cbpa.2008.03.016","article-title":"The impact of natural products upon modern drug discovery","volume":"12","author":"Ganesan","year":"2008","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10091","DOI":"10.1021\/acs.jmedchem.9b01596","article-title":"Facts, Patterns, and principles in drug discovery: Appraising the Rule of 5 with measured physicochemical data","volume":"63","author":"Tinworth","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1208\/s12248-016-9947-5","article-title":"Lipophilicity in drug development: Too much or not enough?","volume":"18","author":"Yazdanian","year":"2016","journal-title":"AAPS J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1021\/acs.jmedchem.8b01263","article-title":"Clearance in drug design","volume":"62","author":"Smith","year":"2019","journal-title":"J. Med. Chem."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/12\/1805\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:38:29Z","timestamp":1760168309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/12\/1805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,1]]},"references-count":55,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["biom11121805"],"URL":"https:\/\/doi.org\/10.3390\/biom11121805","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202111.0125.v1","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,1]]}}}