Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)
Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/12/3674 |
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| author | Samson O. Oselusi Samuel A. Egieyeh Alan Christoffels |
| author_facet | Samson O. Oselusi Samuel A. Egieyeh Alan Christoffels |
| author_sort | Samson O. Oselusi |
| collection | DOAJ |
| description | Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious and time-consuming process of conducting the necessary preclinical tests on these compounds. In this study, cheminformatic profiling was performed on 111 anti-MRSA NPs (AMNPs), using a few orally administered conventional drugs for MRSA (CDs) as reference, to identify compounds with prospects to become drug candidates. This was followed by prioritizing these hits and identifying the liabilities among the AMNPs for possible optimization. Cheminformatic profiling revealed that most of the AMNPs were within the required drug-like region of the investigated properties. For example, more than 76% of the AMNPs showed compliance with the Lipinski, Veber, and Egan predictive rules for oral absorption and permeability. About 34% of the AMNPs showed the prospect to penetrate the blood–brain barrier (BBB), an advantage over the CDs, which are generally non-permeant of BBB. The analysis of toxicity revealed that 59% of the AMNPs might have negligible or no toxicity risks. Structure–activity relationship (SAR) analysis revealed chemical groups that may be determinants of the reported bioactivity of the compounds. A hit prioritization strategy using a novel “desirability scoring function” was able to identify AMNPs with the desired drug-likeness. Hit optimization strategies implemented on AMNPs with poor desirability scores led to the design of two compounds with improved desirability scores. |
| first_indexed | 2024-03-10T10:21:56Z |
| format | Article |
| id | doaj.art-e76c1c692fb84cf9938c94d10d7fb4cc |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:21:56Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e76c1c692fb84cf9938c94d10d7fb4cc2023-11-22T00:21:30ZengMDPI AGMolecules1420-30492021-06-012612367410.3390/molecules26123674Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)Samson O. Oselusi0Samuel A. Egieyeh1Alan Christoffels2School of Pharmacy, University of the Western Cape, Bellville, Cape Town 7535, South AfricaSchool of Pharmacy, University of the Western Cape, Bellville, Cape Town 7535, South AfricaSouth African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town 7535, South AfricaSeveral natural products (NPs) have displayed varying in vitro activities against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious and time-consuming process of conducting the necessary preclinical tests on these compounds. In this study, cheminformatic profiling was performed on 111 anti-MRSA NPs (AMNPs), using a few orally administered conventional drugs for MRSA (CDs) as reference, to identify compounds with prospects to become drug candidates. This was followed by prioritizing these hits and identifying the liabilities among the AMNPs for possible optimization. Cheminformatic profiling revealed that most of the AMNPs were within the required drug-like region of the investigated properties. For example, more than 76% of the AMNPs showed compliance with the Lipinski, Veber, and Egan predictive rules for oral absorption and permeability. About 34% of the AMNPs showed the prospect to penetrate the blood–brain barrier (BBB), an advantage over the CDs, which are generally non-permeant of BBB. The analysis of toxicity revealed that 59% of the AMNPs might have negligible or no toxicity risks. Structure–activity relationship (SAR) analysis revealed chemical groups that may be determinants of the reported bioactivity of the compounds. A hit prioritization strategy using a novel “desirability scoring function” was able to identify AMNPs with the desired drug-likeness. Hit optimization strategies implemented on AMNPs with poor desirability scores led to the design of two compounds with improved desirability scores.https://www.mdpi.com/1420-3049/26/12/3674cheminformaticsprofilingnatural productsmethicillin-resistant <i>Staphylococcus aureus</i> (MRSA), hit prioritizationhit-to-lead optimizationdrug-likeness |
| spellingShingle | Samson O. Oselusi Samuel A. Egieyeh Alan Christoffels Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) Molecules cheminformatics profiling natural products methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), hit prioritization hit-to-lead optimization drug-likeness |
| title | Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) |
| title_full | Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) |
| title_fullStr | Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) |
| title_full_unstemmed | Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) |
| title_short | Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA) |
| title_sort | cheminformatic profiling and hit prioritization of natural products with activities against methicillin resistant i staphylococcus aureus i mrsa |
| topic | cheminformatics profiling natural products methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), hit prioritization hit-to-lead optimization drug-likeness |
| url | https://www.mdpi.com/1420-3049/26/12/3674 |
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