**1. Introduction**

Cyclic peptides have several desirable qualities, including high binding affinity, target selectivity, and low toxicity, which make them a promising therapeutic development approach. Antimicrobial peptides (AMPs), also known as host defense peptides, are short, positively charged peptides found in a wide range of life forms, including microbes and humans. The majority of AMPs are capable of directly killing microbial infections, whereas some operate indirectly by altering the host defensive mechanisms [1].

Teicoplanin, a therapeutically utilized glycopeptide antibiotic, has surfaced as a possible antiviral in the context of the global COVID-19 pandemic, with its potency being increased with lipophilic modifications. Teicoplanin was obtained from *Actinoplanes teichomyceticus*, which was recovered from a soil sample collected in Nimodi Village, Indore, India, for the first time in 1978. Teicoplanin's structure was discovered in 1984. Teicoplanin has been identified as a lipoglycopeptide antibiotic. This antibiotic is made up of a heptapeptide made up of seven aromatic amino acids, sugar residues, and a lipid chain that is nonribosomal. It is made up of five identical chemicals that differ in their fatty acid side chains and are generated by bacteria [2]. This glycopeptide antibiotic typically used to treat Gram-positive bacterial infections has been demonstrated to diminish SARS-CoV-1 and MERS-CoV infection [3].

Lipophilic modifications have been shown to improve the antiviral spectrum and efficacy of glycopeptide antibiotics, which improve antiviral activity against coronaviruses, HIV, flavivirus, and influenza viruses with the drawback of being associated with substantial cytotoxicity [4–13]. To obtain efficient glycopeptide antibiotics by increasing their lipophilicity and avoiding the cytotoxicity problems, recent research has been presented with a study of the structural and biochemical properties of new lipophilic apocarotenoid conjugates of Teicoplanin and its pseudoaglycone [14].

Inspired by this latest research and as a follow up of our previous studies on the chemical reactivity properties of carotenoids [15–19] and cyclopeptides [20–24], we think that it is worth reporting the physicochemical and bioactivity properties of some of these apocarotenoid conjugates of Teicoplanin as well as to predict and understand their chemical reactivity properties considering a methodology developed by our research group. This will be done as a means of further validation of the procedure and for assessing the behavior of the MN12SX density functional in the fulfillment of the Janak theorem and the Ionization Energy Theorem, which is a corollary of the former [25–29].

Thus, the objective of this work is to report the results of a computational study of the bioactivity properties and chemical reactivity of three apocarotenoid conjugates of Teicoplanin based on the CDFT-based Computational Peptidology (CDFT-CP) methodology [20–24]. These three molecules will be designed by considering the Teicoplanin A3–1 variant (PubChem CID 15122170) and the apocarotenoids Bixin, Methylcrocetin and -apo-8'-Carotenoic Acid. The methodology will be based on the combination of the chemical reactivity descriptors from Conceptual Density Functional Theory (CDFT) [30–35] with some Cheminformatics tools [36–43] which may be utilized to assess the associated physicochemical properties. This will be complemented by the detection of the ability of the three molecules to act as possible useful drugs through an analysis of their bioactivities and pharmacokinetics characteristics linked to the ADMET features [44–46].
