Abstract
Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant Staphylococcus aureus (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.
Highlights
The incidence of bacterial resistance to antibiotics is growing at an alarming rate across the globe
This study was set out to profile anti-methicillinresistant Staphylococcus aureus (MRSA) natural products (NPs) (AMNPs) for drug-likeness and to identify their potential for “hit- to-“lead” optimization
The datasets consist of 111 AMNPs with their bioactivity obtained from a recent literature search (Table S1, in the Supplementary Material)
Summary
The incidence of bacterial resistance to antibiotics is growing at an alarming rate across the globe. It is one of the major causes of morbidity, mortality, and economic burden [1,2,3]. A more serious concern the failure of pharmaceutical industries to develop new antibiotics because of poor economic returns and regulatory obstacles [2]. All these have contributed to the growing rate of resistance among pathogenic organisms
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