{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T02:27:04Z","timestamp":1785032824615,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science, Technology and Innovation Plan (MAARIFAH), the King Abdul-Aziz City for Science and Technology (KACST), Kingdom of Saudi Arabia","award":["14-MED2474-10"],"award-info":[{"award-number":["14-MED2474-10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Malaria causes about half a million deaths per year, mainly in children below 5 years of age. Cytoadherence of Plasmodium falciparum infected erythrocytes in brain and placenta has been linked to severe malaria and malarial related deaths. Cytoadherence is mediated by binding of human receptor gC1qR to the DBL\u03b212 domain of a P. falciparum erythrocyte membrane protein family 1 (PfEMP1) protein. In the present work, molecular dynamic simulation was extensively studied for the gC1qR-DBL\u03b212 complex. The stabilized protein complex was used to study the protein\u2013protein interface interactions and mapping of interactive amino acid residues as hotspot were performed. Prediction of inhibitors were performed by using virtual protein\u2013protein inhibitor database Timbal screening of about 15,000 compounds. In silico mutagenesis studies, binding profile and protein ligand interaction fingerprinting were used to strengthen the screening of the potential inhibitors of gC1qR-DBL\u03b212 interface. Six compounds were selected and were further subjected to the MAIP analysis and ADMET studies. From these six compounds, the compounds 3, 5, and 6 were found to outperform on all screening criteria from the rest selected compounds. These compounds may provide novel drugs to treat and manage severe falciparum malaria. Additionally. the identified hotspots can be used in future for designing novel interventions for disruption of interface interactions, such as through peptides or vaccines. Futher in vitro and in vivo studies are required for the confirmation of these compounds as potential inhibitors of gC1qR-DBL\u03b212 interaction.<\/jats:p>","DOI":"10.3390\/ph15060691","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:24:29Z","timestamp":1653989069000},"page":"691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Silico Prediction of Plasmodium falciparum Cytoadherence Inhibitors That Disrupt Interaction between gC1qR-DBL\u03b212 Complex"],"prefix":"10.3390","volume":"15","author":[{"given":"Abdul","family":"Hafiz","sequence":"first","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowaida","family":"Bakri","sequence":"additional","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alsaad","sequence":"additional","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Obadah M.","family":"Fetni","sequence":"additional","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"},{"name":"King Faisal Hospital, Makkah 24236, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lojain I.","family":"Alsubaihi","sequence":"additional","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"},{"name":"Prince Sultan Armed Forces Hospital, Madinah 42375, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hina","family":"Shamshad","sequence":"additional","affiliation":[{"name":"College of Medicine, Umm AL Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2016). World Malaria Report 2021, World Health Organization. Available online: https:\/\/www.who.int\/teams\/global-malaria-programme\/reports\/world-malaria-report-2021."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-018-2195-7","article-title":"Adjunctive therapy for severe malaria: A review and critical appraisal","volume":"17","author":"Varo","year":"2018","journal-title":"Malar. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.cmi.2014.12.011","article-title":"Duration of residency in a non-endemic area and risk of severe malaria in African immigrants","volume":"21","author":"Wyss","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1017\/S0031182015001249","article-title":"Immunity to malaria in an era of declining malaria transmission","volume":"143","author":"Fowkes","year":"2016","journal-title":"Parasitology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e338","DOI":"10.1016\/S1473-3099(19)30261-0","article-title":"Antimalarial drug resistance in Africa: The calm before the storm?","volume":"19","author":"Conrad","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","unstructured":"World Health Organization (WHO) (2021). WHO Malaria Policy Advisory Group (MPAG) Meeting: Meeting Report, World Health Organization."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Shamshad, H., Bakri, R., and Mirza, A.Z. (2022). Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: Successful targets against some infectious diseases. Mol. Biol. Rep., 1\u201333.","DOI":"10.1007\/s11033-022-07266-8"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e9164","DOI":"10.15252\/emmm.201809164","article-title":"Cerebral malaria is associated with differential cytoadherence to brain endothelial cells","volume":"11","author":"Storm","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1046\/j.1365-2958.2003.03570.x","article-title":"Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria","volume":"49","author":"Salanti","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1371\/journal.ppat.0030130","article-title":"Plasmodium falciparum uses gC1qR\/HABP1\/p32 as a receptor to bind to vascular endothelium and for platelet-mediated clumping","volume":"3","author":"Biswas","year":"2007","journal-title":"PLoS Pathog."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mayor, A., Hafiz, A., Bassat, Q., Rovira-Vallbona, E., Sanz, S., Machevo, S., Aguilar, R., Cister\u00f3, P., Siga\u00faque, B., and Men\u00e9ndez, C. (2011). Association of severe malaria outcomes with platelet-mediated clumping and adhesion to a novel host receptor. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019422"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Magall\u00f3n-Tejada, A., Machevo, S., Cister\u00f3, P., Lavstsen, T., Aide, P., Rubio, M., Jim\u00e9nez, A., Turner, L., Valmaseda, A., and Gupta, H. (2016). Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1006011"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bakri, R., Rehan, M., Shamshad, H., and Hafiz, A. (2021). Computational insights into the interaction between cytoadherence receptor gC1qR and the DBL\u03b212 domain of a plasmodium falciparum PfEMP1 ligand. Life, 11.","DOI":"10.3390\/life11090993"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41392-020-00269-6","article-title":"Recent advances in the development of protein\u2013protein interactions modulators: Mechanisms and clinical trials","volume":"5","author":"Lu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","first-page":"139","article-title":"Pevzner Inhibitors of Protein-Protein Interactions (PPIs): An Analysis of Scaffold","volume":"176","author":"Ran","year":"2017","journal-title":"Physiol. Behav."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular Docking: A Powerful Approach for Structure-Based Drug Discovery","volume":"7","author":"Meng","year":"2011","journal-title":"Curr. Comput.-Aided Drug Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.34040\/IJCB.5.1.2015.68","article-title":"Insilico Drug Prediction and Validation of Lead Candidates on Plasmodium Falciparum Erythrocyte Membrane Protein 1(Pfemp1) Against Malaria","volume":"5","author":"Mujawar","year":"2015","journal-title":"Int. J. Comput. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"bat039","DOI":"10.1093\/database\/bat039","article-title":"Database update TIMBAL v2: Update of a database holding small molecules modulating protein\u2014Protein interactions","volume":"2013","author":"Higueruelo","year":"2013","journal-title":"Database"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.2174\/138920012799362909","article-title":"Computational Prediction of Protein Hot Spot Residues","volume":"18","author":"Zhang","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/prot.25748","article-title":"Extraction of molecular features for the drug discovery targeting protein-protein interaction of Helicobacter pylori CagA and tumor suppressor protein ASSP2","volume":"87","author":"Junaid","year":"2019","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"pl2","DOI":"10.1126\/stke.2192004pl2","article-title":"Computational Alanine Scanning of Protein-Protein Interfaces","volume":"2004","author":"Kortemme","year":"2004","journal-title":"Sci. STKE"},{"key":"ref_22","unstructured":"Chemical Computing Group ULC (2013). Molecular Operating Environment, Chemical Computing Group ULC."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"141","DOI":"10.4137\/BBI.S25928","article-title":"PPcheck: A webserver for the quantitative analysis of protein-protein interfaces and prediction of residue hotspots","volume":"9","author":"Sukhwal","year":"2015","journal-title":"Bioinform. Biol. Insights"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kr\u00fcger, D.M., Garz\u00f3n, J.I., Chac\u00f3n, P., and Gohlke, H. (2014). DrugScorePPI knowledge-based potentials used as scoring and objective function in protein-protein docking. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089466"},{"key":"ref_25","unstructured":"(2022, April 03). National Library of Medicine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov."},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13321-021-00487-2","article-title":"MAIP: A web service for predicting blood-stage malaria inhibitors","volume":"13","author":"Bosc","year":"2021","journal-title":"J. Cheminform."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shamshad, H., Saeed, M., Ul-Haq, Z., Halim, S.A., Gul, S., and Mirza, A.Z. (2021). Relative assessment of different statistical instruments and measures for the prediction of promising outcomes using docking, virtual screening and ADMET analysis against HIV-RT. J. Biomol. Struct. Dyn., 1\u201313.","DOI":"10.1080\/07391102.2021.1900915"},{"key":"ref_29","first-page":"11","article-title":"Current Challenges and Opportunities in Designing Protein-Protein Interaction Targeted Drugs","volume":"13","author":"Shin","year":"2020","journal-title":"Adv. Appl. Bioinform. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13369","DOI":"10.1038\/s41598-021-92825-5","article-title":"Exploring the chemical space of protein\u2013protein interaction inhibitors through machine learning","volume":"11","author":"Choi","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13045-020-00850-0","article-title":"The design and development of covalent protein-protein interaction inhibitors for cancer treatment","volume":"13","author":"Cheng","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_33","unstructured":"Turner, P. (2008). XMGRACE, Center for Coastal and Land-Margin Research; Oregon Graduate Institute of Science and Technology. Version 5.1. 19."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph. Model."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1747-0285.2009.00889.x","article-title":"Atomic interactions and profile of small molecules disrupting protein-protein interfaces: The TIMBAL database","volume":"74","author":"Higueruelo","year":"2009","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_36","unstructured":"BIOVIA, Dassault Syst\u00e8mes (2019). BIOVIA Discovery Studio Visualizer, Dassault Systems. Version 2020."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/6\/691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:22:42Z","timestamp":1760138562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/6\/691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ph15060691"],"URL":"https:\/\/doi.org\/10.3390\/ph15060691","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]}}}