Carcinogenicity profile and rat acute toxicity LD50 values confirmed that all studied compounds are noncarcinogenic. these receptors are extremely stable proteins, so it is very difficult to unstable the stability Azoramide of these proteins through utilizing individual drugs. Hence, we studied the combination and tricombination therapy between bioactive compounds which have the best binding affinity and some antiviral drugs like chloroquine, hydroxychloroquine, azithromycin, simeprevir, baloxavir, lopinavir, and favipiravir to show the effect of combination and tricombination therapy to disrupt the stability of the three major viral targets that are mentioned previously. Also, ADMET study suggested that most of all studied bioactive compounds are safe and nontoxic compounds. All results confirmed that caulerpin can be utilized as a combination and tricombination therapy along with the studied antiviral drugs for disrupting the stability of the three major viral receptors (6LU7, 6VYB, and 1R42). Supplementary Information The online version contains Azoramide supplementary material available at 10.1007/s11224-020-01723-5. sp. sp. Accumulation inhibition, antitumor, antiviral, and anti-inflammatory activitiesKjellmanianone (6)Brown macroalgaeand (octanol/water partition coefficient) calculating CD36 the molecule lipophilicity must be not larger than five. (ii) A molecular weight (MW) must be less than 500?Da. (iii) Hydrogen bond donors (nON) must be not more than five. (iv) Hydrogen bond acceptors (nOHN) must be not more than 10. The topological polar surface area (TPSA) must be not more than 160??; it calculates the drug molecule bioavailability and it links to the potential of the hydrogen bonding of the compound. The drug likeness of all studied compounds and antiviral drugs was computed and is summarized in Table ?Table4.4. As shown in Table ?Table4,4, all studied bioactive compounds followed Lipinskis rule of five and are expected to be orally active except compounds 5 and 9. We can measure some features using the ADMET Azoramide profile database such as bloodCbrain barrier (BBB) penetration, human intestinal absorption (HIA), Caco2 cell permeability, CYP inhibitory promiscuity, AMES toxicity, carcinogenicity, and rat acute toxicity LD50 which can help us to report the capability of the studied compounds to act as potential drug leads. All ADMET properties of all studied compounds and antiviral drugs are calculated and displayed in Table ?Table5.5. As shown in Table ?Table5,5, all studied compounds may cross the bloodCbrain barrier (BBB) and absorb in the human intestine (HIA) along the permeability for Caco2 cells, whereas compound 5 showed a negative result for BBB, HIA, and Caco2 cell permeability. Also, all studied compounds were nontoxic and, according to the cytochrome P450 (CYP) values, indicate that all studied compounds are non-substrate and non-inhibitor of CYP enzymes [26, 37]. Carcinogenicity profile and rat acute toxicity LD50 values confirmed that all studied compounds are noncarcinogenic. Also, ADMET property and molecular property descriptors of all studied compounds are in good agreement with those of studied antiviral drugs as shown in Tables?4 and ?and5.5. From the previous studies in this section, we can confirm that most of the studied compounds can act as potential drug leads, except compound 5. Table 4 Prediction of molecular property descriptors of all studied bioactive compounds
1282.00126.1087.0832.412428.00227.11135.68150.553428.00227.16138.7821.264368.00010035.495750.004109.20207.4238.426186.0015??0.6041.6846.007196.0013??1.4051.60150.888256.00125.5577.9436.199712.004103.39187.9225.8710398.00243.94114.1336.76Chloroquine319.9134.62122.7628.80Hydroxychloroquine335.9243.64125.5448.61Azithromycin749.005114.00212.76180.00Simeprevir749.922104.80178.98194.00Baloxavir483.21434.87156.6587.14Lopinavir628.80455.90189.76120.65Favipiravir157.1224??0.60123.5484.60 Open in a separate window Table 5 Prediction of ADMET descriptors of all studied bioactive compounds
1BBB+HIA+Caco2+LowNontoxicNoncarcinogenic1.952BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.293BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.384BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.605BBB-HIA-Caco2 -LowNontoxicNoncarcinogenic2.176BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.187BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.218BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.759BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.7010BBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.23ChloroquineBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.21HydroxychloroquineBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.15AzithromycinBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.23SimeprevirBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.29BaloxavirBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.34LopinavirBBB+HIA+Caco2+LowNontoxicNoncarcinogenic2.70 Open in a separate window Combination therapy The global energy of interacted molecules was associated with free binding energy and their higher negative value explains higher binding probability. Based on the molecular docking study, it was noticed that the predicted antiviral activity of caulerpin (compound 10) against SARS-CoV-2 3-chymotrypsin-like protease, SARS-CoV-2 spike protein, and a host target human angiotensin-converting enzyme 2 (ACE2) receptors is larger than those of all drugs in this study. In this section, we study the combination therapy of compounds yielding the highest.