Eclet. Quim. 50 | e-1594, 2025 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 1/14 1University of Ibadan, Department of Chemistry, Ibadan, Nigeria. 2Federal University of Lokoja, Department of Chemistry, Lokoja, Nigeria. 3Ladoke Akintola University of Technology, Department of Pure and Applied Chemistry, Ogbomoso, Nigeria. 4Osun State University, Department of Pure and Applied Chemistry, Osogbo, Nigeria. 5University of Ilesa, Department of Industrial Chemistry, Ilesa, Nigeria. 6University of Ilesa, Good Health and Wellbeing Research Clusters, Ilesa, Nigeria. +Corresponding author: Banjo Semire, Phone: +2348038269809, Email address: bsemire@lautech.edu.ng Original Article Molecular modeling and pharmacokinetics studies of sulfamidophosphonate derivatives as potential candidate against Staphylococcus aureus Abimbola Modupe Olatunde1 , Kehinde Gabriel Obiyenwa2 , Tofunmi Emmanuel Oladuji3 , Dayo Felix Latona4 , Abel Kolawole Oyebamiji5,6 , Nathaniel Oladoye Olatunji3 , Banjo Semire2,3+ Abstract In silico methods were used in this paper to assess the anti-bacterial activity of Sulfamidophosphonate derivatives against Staphylococcus aureus proteins (1XSD and 4WK3) using molecular docking and ADMET analysis. The results showed that binding affinity (ΔG kJ/mol) ranged from –4.1(NAM) to –7.1 kJ/mol (NAL) for 1XSD, and –5.0 (NAE) to –6.7 kJ/mol (NAM) for 4WK3. Therefore, compounds NAH, NAL, NAN, NAI, NAJ, NAK, 5AD and NAM could be more desirable as inhibitors than Penicillin (–6.0 kJ/mol for 1XSD and –5.4 kJ/mol for 4WK3) in the treatment of Staphylococcus aureus; but ADMET profile revealed that compounds NAF, NAI, NAK NAN and 5AC present attractive pharmacokinetic properties. In this study, compounds NAH, NAL, NAI and NAJ exhibited stronger affinities than the standard (penicillin) against BlaI repressor in complex with DNA (PDB ID: 1XSD) suggesting better inhibitory potential than the standard drug. Article History Received September 02, 2024 Accepted December 19, 2024 Published June 26, 2025 Keywords 1. phytochemicals; 2. bacteria; 3. interactions; 4. ADMET. Section Editors Assis Vicente Benedetti Highlights The antibacterial activity of sulfamidophosphonate derivatives was evaluated. Descriptors found from optimized sulfamidophosphonate derivatives were identified. Nonbonding interactions between drugs and the studied targets were observed. https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://ror.org/03wx2rr30 https://ror.org/018ced875 https://ror.org/043hyzt56 https://ror.org/043hyzt56 https://ror.org/00e16h982 https://ror.org/0019ead15 https://ror.org/0019ead15 https://ror.org/0019ead15 mailto:abimbolatunde1@gmail.com mailto:obiyenwagab@gmail.com mailto:oladutoem@gmail.com mailto:dayo.felix@uniosun.edu.ng mailto:abeloyebamiji@gmail.com mailto:olatuj@gmail.com mailto:bsemire@lauctech.edu.ng https://orcid.org/0000-0002-2545-7723 https://orcid.org/0000-0003-0184-8807 https://orcid.org/0009-0008-9189-4607 https://orcid.org/0000-0002-2722-6734 https://orcid.org/0000-0002-8932-6327 https://orcid.org/0009-0006-4026-3384 https://orcid.org/0000-0002-4173-9165 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 2/14 1. Introduction Bacterial diseases such as tuberculosis, anthrax, pneumonia and osteomyelitis, among others, are deadly and have a significant impact on public health. Staphylococcus aureus is both a commensal bacterium and a human pathogen. About 30% of the human population is colonized with S. aureus (Wertheim et al., 2005). In the early 1930s, doctors began to employ a more efficient test to determine the presence of an S. aureus infection by means of coagulase testing, which helped to detect the enzyme produced by the bacterium. Before the 1940s, S. aureus infections were deadly in most patients until the discovery of penicillin. However, the Meca gene carried by Methicillin-resistant Staphylococcus Aureus (MRSA) encodes the protein PBP-2a (penicillin-binding protein 2a) marked the outbreaks of the resistant strain of this bacterium family (Orent, 2006). The PBP-2a is a penicillin-binding protein (PBP), or an essential bacterial cell wall enzyme that catalyzes the production of the peptidoglycan in the bacterial cell wall. PBP-2A has a lower affinity to bind to beta-lactams (and other penicillin- derived antibiotics) when compared to other PBPS. The PBP-2A continues to catalyze the synthesis of the bacterial cell wall even in the presence of many antibiotics (Rasigade, 2014). The chemistry of heterocyclic molecules plays a huge role in the development of effective drugs for bacterial, fungal and viral diseases. Heterocyclic compounds are the most important organic compounds that present great interest in medicinal chemistry (Arora et al., 2012; Winum et al., 2006). Sulfonamide derivatives, a class of heterocyclic compounds in which many this class compounds have been reported to show biological activities such as anti-mycobacterial, anticonvulsant, anti-hypoglycemic, anticancer, and enzyme inhibition (Farhan et al., 2018; Hu et al., 2008; Supuran, 2017; Zhao et al., 2019). Sulfonamide derivatives are attractive due to their diverse biological targets and practical therapeutic ability with minimal side effects (Hu et al., 2008; Ratchanok, 2021). Presently, there have been a remarkable advance in the development of new potent antibiotics for combating antimicrobial resistance (Bazine et al., 2020a; Masters et al., 2003); however, the microorganisms are getting resistant to the existing antibiotic classes by mutation of membrane permeability and spore formation to the drugs (Forgacs et al., 2009) thereby adapting themselves to withstand the potency of the drug. This has led to continuous research on drug development and discovery to produce new drugs that can fight the resistance caused by Staphylococcus Aureus. In recent times, Sulfamidophosphonate, a sulfonamide and cyclosulfamide derivative, have been a focus of chemical and biological researchers for the development of new drugs, due to its wide range of biological and physical properties (Krátký et al., 2012; Waring et al., 2015). In this study, computational methods, including molecular docking and ADMET profiling to evaluate antibacterial activities of some selected Sulfamidophosphonate derivatives based on the work of Bazine et al. (2020b). These compounds are 1-(1,1-dioxo-1λ6,2,5- thiadiazolidin-2-yl)(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)(1,1- diethoxyphosphonate (5AD), 1,1-(3-methylphenyl- sulfonamidyl)(6-methyl-3,4-dihydroquinolin-2(1H)- onyl)methyl)(1,1-diethoxy)phosphonate (NAI), 1,1-(3- methylphenyl-sulfonamidyl)(3,4-dihydroquinolin-2(1H)- onyl)methyl)(1,1-diethoxy)phosphonate (NAH), 1,1-(phenyl- sulfonamidyl)(6-methyl-3,4-dihydroquinolin-2(1H)- onyl)methyl)(1,1-diethoxy)phosphonate (NAJ), 1,1-(2- methylphenyl-sulfonamidyl)(3,4-dihydroquinolin-2(1H)- onyl)methyl)(1,1-diethoxy)phosphonate (NAK), 1,1-(3- methylphenyl)-sulfonamidyl)(2-methyl-3,4-dihydroquinolin- 2(1H)-onyl)methyl)(1,1-diethoxy)phosphonate (NAL), 1,1-(3- chlorophenyl)-sulfonamidyl)(2-methyl-3,4-dihydroquinolin- 2(1H)-onyl)methyl)(1,1-diethoxy)phosphonate (NAM), and 1,1- (2-hydroxylphenyl)-sulfonamidyl)(2-methyl-3,4-dihydroquinolin- 2(1H)-onyl)methyl)(1,1-diethoxy)phosphonate (NAN). 2. Details of research methods 2.1. Geometry optimization of the ligands The conformer search was carried out on each sulfamidophosphonate using the DFT method to find the conformer with the lowest energy for each compound, which was then taken as the equilibrium geometry structure of the compound. The equilibrium optimization was performed on the ligands (Fig. 1) with DFT in correlation with Becke’s three-parameter hybrid functional with a correlation of Lee, Yang and Parr (B3LYP) (Becke, 1993; Hehre et al., 1988; Parr et al., 1999; Yang et al., 2005; Lee et al., 1988) with 6-31G(d,p) basis set. Quantum chemical reactivity descriptors of the sulfamidophosphonates such as frontier orbital energies, which are the highest occupied molecular orbital energy (EHOMO), the lowest unoccupied molecular orbital energy (ELUMO) and band energy gap (E(HOMO– LUMO); chemical hardness (η = EHOMO−ELUMO 2 ); chemical softness (σ = 1 2𝜂 ); chemical potential (μ = ( 𝐸𝐻𝑂𝑀𝑂+ 𝐸𝐿𝑈𝑀𝑂 2 ); global electrophilicity (ω = μ2 2η = (IP+EA)2 4(IP−EA) ); electron donating power (ω– = ( 3𝐼𝑃+𝐸𝐴 )2 16(𝐼𝑃−𝐸𝐴) ) and electron accepting power (ω+ = ( 𝐼𝑃+3𝐸𝐴 )2 16(𝐼𝑃−𝐸𝐴) ) were estimated form the optimized structures (Flores-Holguín et al., 2019; Manzanilla and Robles, 2020; Ramírez-Martínez et at., 2023). 2.2. Molecular docking procedures The optimized ligands were docked into the receptors by using Autodock Tool 1.5.6., AutoDock Vina 1.1.2, Edupymol version 1.7.4.4 and Discovery studio. The receptors/proteins were cleaned up and repaired with Discovery Studio software, and Edupymol was used to visualize the docking results as described (Adegbola et al., 2021a; Adepoju et al., 2022; Oyebamiji et al., 2021). The binding pocket of the protein, as determined in the 3D structure using Discovery Studio and the Autodock tool, was used to prepare the protein. Polar hydrogens were added to the protein, followed by Kolleman charges, before setting the grid box. Using Auto Grid, the grid box center (x = –5.252, y = 9.613, z = 36.518) and size (x = 58, y = 52, z = 66) for BlaI repressor in complex with DNA (PDB ID: 1XSD), and (center: x = 0.043, y = 2.734, z = 85.68) and (size: x = 48, y = 40, z = 40) for 4WK3 receptor were set. The receptor and ligand were then saved as PDBQT files. The Docking simulations were then performed using Autodock Vina (Trott et al., 2010) for the calculations of binding affinity, as well as studying non-bonding interactions (hydrophobic interactions) and hydrogen bonding between the ligand and proteins, which were visualized using Discovery Studio 2019. https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 3/14 NAH NAI NAJ NAM NAK NAL NAN 5AD Figure 1. Optimized structures of studied sulfamidophosphonates. Source: Elaborated by the authors. 2.3. ADME/pharmacokinetic predictions The smiles of optimized structures of the studied ligands were used for physicochemical and ADMET profiles to assess the qualitative pharmacokinetics properties via; absorption, distribution, metabolism, excretion and toxicity by using ADMET Predictor (http://biosig.unimelb.edu.au/pkcsm/prediction). These early assessments of pharmacokinetic and toxic properties are essential step in drug discovery, although the process of drug discovery and development is a very complex, lengthy and cost- intensive; drug development failures have been attributed to poor pharmacokinetics and bioavailability (Adegbola et al., 2021b; Daina and Zoete, 2016). Therefore, ADMET properties play a crucial role in every stage of drug discovery and development, aiming to reduce likely challenges associated with clinical trial treatments (Darvas et al., 2002). 3. Results and discussion 3.1. Molecular quantum reactivity descriptors The frontier orbital (the HOMO and LUMO) energies are very essential to the molecular stability and responses to the surrounding molecules, where HOMO and LUMO represent the highest occupied molecular orbital and the lowest unoccupied molecular orbital, respectively. The high HOMO energy (or low ionization energy, IP) typifies the enhancement of a ligand to donate electrons to the neighboring molecule. Lower LUMO energy, on the other hand (or high electron affinity, EA), represents a ligand's ability to accept electrons from the neighboring compounds (Oyebamiji and Semire, 2016). The lower IP values revealed that NAH (4.05 eV), 5AD (5.47 eV), and NAN (5.75 eV) should be able to donate electrons readily to the https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 http://biosig.unimelb.edu.au/pkcsm/prediction Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 4/14 surrounding molecule than Penicillin (9.61 eV) and Sulfamethoxazole (5.93 eV) (Oyeneyin, 2023). Also, all the compounds, especially NAL, NAH, 5AD, NAM, and NAN, should have enhanced electron-accepting tendency from the neighboring molecule (Table 1). Low polarizability, low reactivity, stronger stabilization and interactions between a molecule and its receptor favor molecules with a larger energy gap (Eg), whereas a smaller energy gap favors high reactivity, high polarizability, weaker stabilization and interactions of a molecule with neighboring compound. Therefore, higher values, Eg, η and σ, showed that penicillin and Sulfamethoxazole are more stable, which may support strong interactions, although NAJ, NAI, NAK and NAM may also display strong interactions (Thanikaivelan et al., 2020). The chemical potential (μ) showed that all the sulfamidophosphonate compounds are more likely to interact strongly through electrostatic interactions with the receptor than the standard drugs (penicillin and Sulfamethoxazole). The difference between electron-donating ability (ω–) and electron- accepting ability (ω+) is ∣∆ω∣, which measures the total responsiveness of a molecule to its surroundings. Higher values typify a strong response leading to strong interactions between the molecule and its surroundings (Asibor et al., 2024). Therefore, NAL, NAM, NAK, NAJ, and 5AD are likely disposed of stronger interactions with the receptor than penicillin and Sulfamethoxazole. Table 1. Quantum chemical descriptors of sulfamidophosphonates using B3LYP/6-31G**. IP EA Eg η σ μ ω ω- ω+ |∆𝝎 | = (𝝎+ − 𝝎−) NAH 4.05 2.68 1.37 0.685 0.730 –3.365 8.265 10.033 6.668 3.365 NAI 6.26 1.81 4.45 2.225 0.225 –4.035 3.659 5.954 1.919 4.035 NAJ 6.11 1.55 4.56 2.280 0.219 –3.830 3.217 5.417 1.587 3.830 NAK 6.33 1.80 4.53 2.265 0.221 –4.065 3.648 5.963 1.898 4.065 NAL 6.47 4.01 2.46 1.230 0.407 –5.240 11.162 13.935 8.695 5.240 NAM 6.22 2.03 4.19 2.095 0.239 –4.125 4.061 6.385 2.260 4.125 NAN 5.75 2.03 3.72 1.860 0.269 –3.890 4.068 6.245 2.355 3.890 5AD 5.47 2.54 2.93 1.465 0.341 –4.005 5.474 7.660 3.655 4.005 Penicillin 9.61 –3.34 12.95 6.475 0.077 –3.135 0.759 3.136 0.001 3.135 Sulfamethoxazole 5.93 0.51 5.42 2.710 0.185 –3.220 1.913 3.862 0.642 3.220 Source: Elaborated by the authors. 3.2. Docking orientation and binding affinity BlaI is a repressor, as well as a beta-lactamase that is responsible for penicillin resistance in Staphylococcus aureus and essential for Staphylococcus aureus reproduction. The BlaI repressor in complex with DNA (PDB ID: 1XSD) was docked with sulfamidophosphonate derivatives. Results were presented in Table 2 and Fig. 2. The binding affinities for all the studied ligands with 1XSD ranged from –17.2 (NAM) to –29.7 (NAL) kJ/mol, these inferred that inhibitory constants (Ki) of the drugs fall between 6.21 μmol/L to 984.0 μmol/L as compared to –25.1 kJ/mol for penicillin, used as standard (Table 2). The H-bond distances between amino acid residues in the binding purse and ligands ranged from 1.9 to 3.50 Å. They exhibited other non-bonding interactions with 1XSD receptor (Fig. 2). Compound/ligand NAL with the highest binding affinity (–29.7 kJ/mol) is hydrogen bonded with ARG'60, TYR'69, ARG'46, ARG' 46 and THR'50 and showed interactions with ALA'27, TYR'67, TYR'69, ARG'46, THR'50 and ARG'60. NAN with the binding affinity of –23.8 kJ/mol displayed H-bond interactions with ARG'60 and TYR 69, and hydrophobic interactions with ARG 46, TYR'69, LYS'54, ALA'27, ARG'60 and THR'50. Also, NAI and NAK with binding affinities of –28.5 and –25.1 kJ/mol, respectively, showed only hydrophobic interactions with PHE'86, LEU'98, PHE'102, TRP'13 and ALA'83 for NAI, and LYS'69, ALA'83, PHE'86 for NAK. Ligand NAJ with a binding affinity of –28.0 kJ/mol hydrophobically interacted with LYS'54 ARG'60 ARG'46 TYR'69, and THR'50, as well as H-bonding with ARG’26 and ARG’60. Also, NAH presented H-Bonding with ARG’26 and ARG’60’ and hydrophobic interactions with ARG'60, TYR'67, ILE'66, and LYS'43. Furthermore, 5AD with a binding affinity of -26.4 kJ/mol is hydrogen-bonded with TYR'59 ARG'46 and TYR'69 and shows hydrophobic interactions with ARG'60 TYR'69 and ARG'46, while NAM with a binding affinity of –17.2 kJ/mol displayed hydrophobic interactions with LYS'43 ARG'46 and TYR'67. Penicillin, which was used as the standard drug, has a binding energy of –25.1 kJ/mol, interacting hydrophobically with ALA'83 ASN'17 and PHE'86. The ionization energy (IP = –EHOMO) and electron affinity (EA = –ELUMO) estimated from the DFT calculations showed that NAL has highest values for both IP (6.47 eV) and EA (4.01 eV) which led to lower energy gap; thus, supported quick electrons transition and donation to the receptor than other compounds. Therefore, NAL, NAH, NAI and NAJ exhibited the most significant inhibitory potential against 1XSD when compared with the standard drug (penicillin). Table 2. Binding affinity and non-bonding interactions of 1XSD and 4WK3 receptors with ligands. Ligand 1XSD 4WK3 Binding Affinity ΔG (kJ/mol) Binding Affinity ΔG (kJ/mol) NAH –26.4 –24.3 NAI –27.6 –24.7 NAJ –28.5 –25.1 NAK –26.8 –25.5 NAL –27.2 –24.3 NAM –25.9 –28.0 NAN –23.8 –28.0 5AD –24.3 –23.0 Penicillin –26.4 –22.6 Sulfamethoxazole –23.4 –22.6 Source: Elaborated by the authors. https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 5/14 2D Structure 3D Structure 1XSD + NAH 1XSD + NAI 1XSD + NAJ https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 6/14 1XSD + NAK 1XSD + NAL 1XSD +NAM https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 7/14 1XSD +NAN 1XSD+ 5AD 1XSD + Penicillin https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 8/14 1XSD + Sulfonamide Figure 2. 2D and 3D of 1XSD with the sulfamidophosphonates showing hydrogen interactions. Source: Elaborated by the authors. The calculated binding affinities for the ligands with 4WK3 receptor showed that the drugs interacted with 4WK3, the bacterial secondary messenger involved in sensing integrity, cell wall metabolism and potassium transport. The binding affinities from the docking results showed that NAK, NAN, 5AD, and NAH presented binding affinities of –23.0, –24.3, –25.1, and –25.5 kJ/mol, respectively. Additionally, NAL, NAJ, NAI, and NAM bind to 4wk3 receptors with affinities of –25.5, –25.9, –27.6, and –28.0 kJ/mol, respectively (Table 2). The H-bond formed between 4WK3 receptor amino acid residues and the drugs is within 3.5 Å. Other hydrophobic interactions of the medications with 4WK3 are displayed in Fig. 3. Compound NAK is H-bonded with LYS'29 and also has hydrophobic interactions with ALA'17, VAL'21, LYS'29 and THR'42; NAJ is hydrogen bonded with ASN'24, GLY'47, GLN'108, ARG'26, and formed hydrophobic interactions with ARG'26, GLN'108, GLY'47, VAL'48, ARG'26 and ARG'52; NAN showed H-bond interactions with ASP'10 THR'42 and LYS'29, hydrophobic interactions with SER'13 LYS'29 and THR'42; 5AD is H-bonded with ARG'26 GLY'47 ARG'26 ASN'24 ARG'26 and ARG'52 and also has hydrophobic interactions with CYS'46 ARG'26 ARG'52, GLN'47 and ARG'26; NAH showed hydrophobic interactions with GLN'14 LYS'29 SER'13 and THR'42; NAL ARG'26 MET'1 PHE'106 GLN'108 GLY'47 ASN'49 and VAL'48; NAI showed hydrophobic interactions with THR'42 GLN'14 SER'13 and LYS'29; NAM showed hydrophobic interactions with VAL'103 PHE'106 THR'28 GLY'47 and ARG'26; whereas Penicillin is H- bonded to ASN'61 ASN'66 and ALA'96, and hydrophobically interacted with ASN'61 ASN'66 and ALA'96 residues (Fig. 4). Although no direct relationship is observed between the frontier energies of the ligands and the binding affinities, those ligands with higher IP presented good binding affinities. The results revealed that compounds NAH, NAL, NAN, NAI, NAJ, 5AD and NAM exhibited significant inhibitions against 4WK3 when compared with the standard drug (penicillin). Complex 2D 3D 4WK3 +NAH https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 9/14 4WK3 +NAI 4WK3 +NAJ 4WK3 +NAK 4WK3 +NAL https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 10/14 4WK3 +NAM 4WK3 +NAN 4WK3 +5AD https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 11/14 4WK3 + PENCILLIN 4WK3 + Sulfameth oxazole Figure 3. 2D and 3D of 4WK3 with sulfamidophosphonates showing hydrogen interactions. Source: Elaborated by the authors. 3.3. Molecular dynamics simulation In this study, the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and actual binding energies for NAJ, NAN, and NAM, as well as the studied drug (Penicillin), were investigated and reported. As shown in Table 3, it was observed that NAJ proved to have the highest strength in inhibiting BlaI repressor (1XSD) than the studied reference compound. Additionally, the report in Table 3 revealed that NAM has the lowest inhibitory activity compared to NAN and the reference compounds. More so, NAN with 2.3 kJ/mol as binding energy is expected to have the highest capacity to inhibit Staphyloccus aureus PstA (PDB ID: 4WK3) than NAM and the reference compound. In this work, the RMSD for NAJ-1XSD and NAN-4WK3 is presented in Figs. 4 and 5. As shown in the exact figures, the extent of deviation of the studied complex from its initial configuration bound to the studied receptor was examined in the calculated RMSD. The simulated system proved stable in the last five ps for the two selected compounds in Table 3. Table 3. Calculated binding Energies for NAJ-1XSD, NAM-4WK3 and NAN-4WK3 with Penicillin-receptor complexes. Complexes Binding Energy Components (kJ/mol) ΔEvdw ΔEele ΔGgas ΔGsol ΔGbind NAJ-1XSD –2.6±0.4 8±1 5±1 1.00±0.04 6.0 ± 1 Penicillin-1XSD –29±2 –32±8 –61±6 79±9 18±3 NAM-4WK3 –2.2±0.5 –0.38±0.08 –0.38±0.08 3.5±0.3 3.1±0.4 NAN-4WK3 –2.1±0.4 0.1±0.1 1. 0 ± 0.1 0.9±0.3 2.3±0.3 Penicillin-4WK3 –2.0±0.4 –0.3±0.2 –0.3±0.2 3±5 2.3±0.3 Source: Elaborated by the authors. https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 12/14 Figure 4. RMSD for NAJ-1XSD and Penicillin-1XSD complexes. Source: Elaborated by the authors. Figure 5. RMSD for NAN-4WK3 and Penicillin-4WK3 complexes. Source: Elaborated by the authors. 3.3. ADME/pharmacokinetic predictions Safety is paramount in drug usage; in this research, the physicochemical and ADMET properties of the ligands were assessed. However, there are lots of drug candidates that are not drug-like. Lipinski’s rule of five (Ro5) was used to access the physicochemical properties of the ligands, which include molecular weight (150 ≤ MW ≤ 500), lipophilicity (log P ≤ 5), number of rotatable bonds (ROTBs ≤ 10), hydrogen bond donor (HBD ≤ 5) and hydrogen bond acceptor (HBA ≤ 10) (Daina et al., 2017; Lipinski et al., 2004). All the compounds and the standard drugs obeyed Lipinski‘s rule for hydrogen bond donors, hydrogen bond acceptors and molecular weight and WLogP. They are moderately soluble in water, whereas standard medicines are highly soluble. However, all the ligands have TPSA values between 132.75 and 165.01 Å, which are higher than 131.6 Å as the upper limit (Table 4). Lack of efficacy and safety are the two major causes leading to drug failure (Sun et al., 2022), which means the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemicals play vital roles in every stage of drug discovery and development. Hence, using ADMET profiling is considered one way to reduce likely challenges associated with clinical trial treatments (Daina and Zoete, 2016; Darvas et al., 2002). Compounds NAH, NAI, NAJ, NAK, NAL, NAM, NAN and 5AD were inhibitors to CYP3A4; therefore, they may cause an elevation in the concentration of the corresponding compounds, leading to drug overdose (Conrad et al., 2024). Additionally, all the compounds except compound NAN exhibit high GI absorption, and none of the compounds possess blood–brain barrier BBB penetration. NAC, NAD, NAE, NAG, NAN, NAF, NAK, NAI, and NAM were identified as Pgp substrates (i.e. they can be transported out of the cell. Additionally, compounds NAD, NAE, and NAF could be inhibitors of Cyp2C19, while compounds NAC, NAG, NAN, NAK, 5AC and NAM could be substrates for Cyp2C19. None of the compounds could be inhibitor of Cyp2C9, and NAC was an inhibitor of Cyp2D6 (Table 5). The ADMET results revealed that NAF, NAI, NAK NAN and 5AC have attractive pharmacokinetic properties (Table 5). Table 4. Physicochemical properties of sulfamidophosphonates. Drugs Mw g/mol Heavy Atoms Aromatic Heavy Atoms Fraction Csp3 Rotatable Bonds HBA HBD Molar Ref TPSA Lipinski violation Log P (o/w) Bio Score H2O solubility NAH 478.50 32 16 0.32 10 7 2 124.79 132.75 0 3.03 0.55 Mod soluble NAI 478.50 32 16 0.32 9 7 2 124.94 132.75 0 3.29 0.55 Mod soluble NAJ 464.47 31 16 0.29 9 7 2 119.98 132.75 0 2.94 0.55 Mod soluble NAK 478.5 32 16 0.32 9 7 2 124.94 132.75 0 3.33 0.55 Mod soluble NAL 478.48 32 16 0.24 9 6 3 126.71 146.72 0 2.84 0.55 Mod soluble NAM 497.48 33 16 0.29 10 8 3 125.11 144.78 0 3.23 0.55 Mod soluble NAN 495.49 33 16 0.29 10 8 4 127.18 165.01 0 0.55 Mod soluble 5AD 429.43 28 10 0.47 7 8 2 114.55 135.96 0 1.49 0.55 Soluble Penicillin 334.39 23 6 0.44 5 4 2 90.54 121.13 0 1.39 0.55 Soluble Sulfameth- oxazole 253.28 17 11 0.1 3 4 2 62.99 106.6 0 -0.15 0.55 Soluble Source: Elaborated by the authors. https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 Original Article https://doi.org/10.26850/1678-4618.eq.v50.2025.e1594 ISSN 1678-4618 page 13/14 Table 5. Pharmacokinetics properties of sulfamidophosphonates. Drugs GI Absorption BBB Permeant p-gp Substrate CYP1A2 Inhibitor CYP2C19 Inhibitor CYP2C9 Inhibitor CYP2D6 Inhibitor CYP3A4 Inhibitor Log Kp (skin Permeation) cm/s NAH Low No Yes No Yes Yes No Yes –7.28 NAI Low No No No Yes Yes No Yes –6.95 NAJ Low No No No Yes Yes No Yes –7.12 NAK Low No No No Yes Yes No Yes –6.95 NAL Low No Yes No No No No Yes –7.25 NAM Low No Yes Yes No No No Yes –7.45 NAN Low No Yes No No No No Yes –7.76 5AD High No Yes No No No No No –8.63 Penicillin High No No No No No No No –6.75 Sulfameth oxazole High No No No No No No No –6.93 Source: Elaborated by the authors. 4. Conclusions This study emphasized an in-silico assessment of anti- bacterial activities of sulfamidophosponate derivatives as compared with standard drugs (Penicillin and Sulfamethoxazole) against target proteins of Staphylococcus aureus via molecular docking and ADMET prediction. In this study, compounds NAH, NAL, NAI and NAJ exhibited stronger affinities than the standard (penicillin) against BlaI repressor in complex with DNA (PDB ID: 1XSD), suggesting a better inhibitory potential than the standard drug. Furthermore, compounds NAH, NAI, NAJ, NAL, NAM, NAN and 5AD potentially inhibit 4WK3 than the standard drug (penicillin). These compounds could be inhibitors with potential for treating bacterial infection. Additionally, the ADMET results revealed that compounds NAG, NAE, NAH, and NAK have attractive pharmacokinetic properties. In general, this study demonstrated that compounds NAF, NAI, NAK and NAN could be potential inhibitors against Staphylococcus aureus, and they possess good pharmacokinetic properties, which are probable for drug discovery. Authors’ contribution Conceptualization: Abimbola Modupe Olatunde, Kehinde Gabriel Obiyenwa; Data curation: Nathaniel Oladoye Olatunji; Kehinde Gabriel Obiyenwa; Formal Analysis: Nathaniel Oladoye Olatunji; Kehinde Gabriel Obiyenwa; Funding acquisition: Abimbola Modupe Olatunde, Kehinde Gabriel Obiyenwa; Investigation: Tofunmi Emmanuel Oladuji, Dayo Felix Latona; Methodology: Abimbola Modupe Olatunde, Kehinde Gabriel Obiyenwa; Project administration: Abel Kolawole Oyebamiji; Banjo Semire; Resources: Tofunmi Emmanuel Oladuji, Dayo Felix Latona; Software: Abel Kolawole Oyebamiji; Banjo Semire; Supervision: Abel Kolawole Oyebamiji; Banjo Semire; Validation: Tofunmi Emmanuel Oladuji, Dayo Felix Latona; Visualization: Abel Kolawole Oyebamiji; Banjo Semire; Writing – original draft: Abel Kolawole Oyebamiji; Banjo Semire; Writing – review & editing: Abel Kolawole Oyebamiji; Banjo Semire. Data availability statement All data sets were generated or analyzed in the current study. 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