Drug-likeness and ADME prediction

The results in Table 3 show that besides obeying Lipinski’s rule of five (Ro5), all derivatives supported the Veber parameters. Their molecular weight, MW ≤ 500 Da (except C-5, C-7, and C-9), log of octanol/water partition coefficient, ILogP < 5, hydrogen bond acceptor (HBA) counts, < 5, hydrogen bond donor (HBD) counts, < 10 (Table 3) showing the excellent drug-like properties of the designed derivatives [25]. Additional parameters, such as topological polar surface area (TPSA) and the number of rotatable bonds (nRotB) were also determined. The TPSA values range between 68.30 and 114.12 Å2 values (Table 3) which are greater than 60 Å2 but less than 140 Å2. Being greater than 60 Å2 indicates poor blood–brain barrier penetration, the excellent intestinal absorption is reflected in the less than 140 Å2 values [27]. The number of rotatable bonds (nRotB) measures the molecular flexibility of the molecule, with a value within ≤ 10. The designed derivatives have their estimated nRotB ranges between 7 and 9. No derivative was found to violate more than one Lipinski parameter, indicating that the proposed derivatives have good oral absorption. The log of octanol/water partition coefficient (LogP), molecular weight (MW), and topological polar surface area (TPSA) values are all factors of both membrane permeability and oral bioavailability. The in silico ADME values determined (Table 4) revealed the skin permeability (log Kp) of the design derivatives to be within − 4.83 to − 5.97 cm/s, which is within the acceptable range of − 8.0 to − 1.0 cm/s [8]. Molar refractivity is the measure of the volume occupied either by an atom or a group of atoms [1]. The designed derivatives have their molar refractivity values ranging from 115.77 to 132.34, and this falls between the recommended range of 40–130 [4] with C-9 as the only exception. The designed derivatives show high gastrointestinal absorptions except in C-1, C-6, C-9, and C-10, while the BBB investigations (Table 4) show the designed derivatives lacking the ability to penetrate BBB. Hence, the use of derivatives in the treatment of cerebral malaria is rendered ineffective. Substances can enter the cell via active transport or passive diffusion, and they can be effluxed through the permeability glycoprotein (Pgp). Except for C-01, which binds to molecules to efflux, the derivatives were all found to lack Pgp substrate. Table 4 shows the findings of the inhibitory prediction of three Cytochrome P450 (CYP) isoforms; CYP1A2, CYP2C9, and CYP2C19. The drug likeliness and in silico ADME predictions made in this study, as well as those made in investigations with quinazolines-based EGFR inhibitors [31], all passed the test.

Molecular docking

Molecular docking studies of the derivatives were carried out in the binding pockets of Pf-DHODH to determine the protein that will bind better with the ligands. The docking results showing the binding affinity between the ligands with Pf-DHODH are shown in Table 5. As shown, the re-rank scores of the derivatives were found to be lower than those of atovaquone and chloroquine standards, a fact supported by the lower binding energies of the ligands with Pf-DHODH than with the standards. The high re-rank scores between the ligands and Pf-DHODH receptor show an excellent binding mode between them. Derivative C-02, {5-((6,7-dimethoxy-4-((3-nitrobenzyl)amino)quinazolin-2-yl)amino)-2-fluorobenzaldehyde} was found to possess the lowest re-rank score and interaction energies of − 173.5280 and − 225.1120 kcal/mol respectively as reflected in Table 6. The derivative binds with various amino acid residues, where eight of such interactions were with Gly277, Phe278, Asn347, Lys429, Gly506, twice with Ile508, and Ala225 residues to produce eight (8) conventional hydrogen bonds with bonds lengths 2.7238 Å, 2.4607 Å, 2.3411 Å, 2.3244 Å, 2.0826 Å, 2.9660 Å, 2.0304 Å, and 2.6270 Å, respectively, as shown in Table 6. The derivative C-02 also shows seven (7) other interactions leading to carbon-hydrogen bonds and an additional two (2) resulting in Pi-donor hydrogen bonds. These docking results were found to be better than those derived from similar research with benzamide derivatives acting on the same protein target, Pf-DHODH [32]. The carbon–hydrogen bonds were with Pro346, Gly507, Ser529, Gly226, Tyr528, Asn458, and Gln526 amino acid residues, while the Pi-donor hydrogen bonds were with Gly507, Ser529 as shown in Table 7. The hydrogen bonds as well as other hydrophobic interactions between the derivative and the receptor could be responsible for the high binding affinity of the derivative. As with derivative C02, the interactions of the next four most active derivatives with the various amino acid residues as well as their 2–3D relation are also shown in Tables 5 and 6. This in silico research revealed the stability of the derived derivatives as a function of hydrogen bonding besides various other interactions with several amino acid residues of the receptor. Hence, derivative C-02 will inhibit P. falciparum better than any other derivatives. The docking validation was carried out to determine the docking procedure by measuring the deviation of the re-docking output from the original docking position. The variance is expressed as a root-mean-square deviation (RMSD) value of 0.793 Å. As a result, the docking procedures are validated and can dock the proposed ligands.

Dynamic simulation

The stability of the proton-ligand complex was assessed in molecular dynamic simulation through the dynamic study of the behavior of the molecular system. As a result, the docked complex of derivative C-02, which had the lowest docking score of − 173.528 kcal/mol, was used for molecular dynamics simulations using the OPLS_2005 force field. The root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration data as a function of time were used to analyze the molecular dynamics simulations. Figure 3 represents the plot of the root-mean-square deviation (RMSD) of the derivative C-02-Pf-DHODH protein (PDB ID: 4CQ8) complex. For the 100-ns simulation time, there is no significant conformational change in the protein structure, showing that the complex is stable. The Pf-DHODH’s RMSD was plotted on the left Y-axis, while that of the ligand aligning on the protein backbone was plotted on the right Y-axis. The complex tends to be stabilized during the course of simulation with respect to the reference frame at time 0 ns. Slight fluctuations can however be seen from the 60 ns. The fluctuation is insignificant, ranging from 0.4 to 1.2 Å (i.e., are within the permissible range of 1–3 Å), showing that the protein has not undergone a severe conformational transformation. The residue interactions of Pf-DHODH with derivative C-02 are shown in Fig. 4A. It shows that all the interactions of docked pose were retained during the simulation time of 100 ns, i.e., molecular interactions with residues Thr459, Asn274, Asn458, Lys429, Ala225, Gly526, and Tyr528. Figure 4B reflects the derivative C-02-Pf-DHODH contacts as stacked bar charts normalized throughout a 100-ns trajectory. The hydrogen bonds, hydrophobic, and ionic interactions, and water bridges are the various categories of ligand–protein contact. During the dynamic simulation, hydrogen bonds, hydrophobic interactions, and water bridges are the main interactions. The hydrogen bonds observed in the docked posed earlier (Lys429 and Ala225) were kept during the dynamic simulation. The root-mean-square fluctuation (RMSF) plot (Fig. 5) measures the fluctuations of every atom in the local domain of the protein and the effect of binding compounds. The protein RMSF (Fig. 5A) shows moderate fluctuations in the binding site residues with an average RMSF value of 1.5 Å, which indicates a lack of significant changes along the protein chain. The ligand RMSF (Fig. 5B) shows a fluctuation ranging between 0.8 and 1.7 Å reflecting the lack of changes in the ligand atom positions. The radius of gyration (Rg) calculates the mass of atoms about the mass of the complex’s center. The Rg data implies that ligand movement inside the binding site influences protein structural compactness. The graph of the radius of gyration of protein (Fig. 6A) shows the Rg value of the protein was initially low within 19.9–20.1 Å and then stabilizes within 2.1–2.3 Å for a long period of simulation time. For the ligand (Fig. 6B), the Rg value was initially 4.8–5.0 Å before stabilizing on an average of 4.8 Å. The graphs also show low fluctuation, showing that the Pf-DHODH-C-02 complex is in a compact state and does not deviate significantly, hence had better interaction during the ligand simulation.

The techniques employed in this research has found various applications in other antimalarial derivatives such as in the top 10 hits in Alzain’s research [2] subjected to ADME calculation. Where, all ten of the compounds show favorable ADME characteristics that will aid in future studies and validations. All of the top 10 compounds fall inside the permitted ranges for absorption, solubility, permeability, and the Lipinski rule and have values that are comparable to those of the reference ligand and DSM265 as well. In the work of Qidwai [24], all of the derivatives of antimalarial compounds have strong binding affinities for the parasite proteins plasmepsin-2 and falcipain-2, according to the docked poses (hemoglobin digesting enzymes). The QSAR model, oral bioavailability, ADME, and toxicity risk assessments indicated that molecules N1, N2, N8, N30, N33, and N39 possess better drug-like qualities than Artemisinin and DHA.

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