Biomedicines, Vol. 11, Pages 85: Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro) Identified from the Library of FDA-Approved Drugs Using Molecular Docking Studies

3.2. In Silico Screening of FDA-Approved Drugs to Identify Potential BindersThe receptor and the FDA-approved drug library preparation for molecular docking studies were performed using Schrödinger Suite, 2019, using the protein preparation wizard and LigPrep modules [26]. The potential sites for drug binding in the crystal structure were discovered using the SiteMap tool [28]. Five potential druggable sites for ligand binding were identified by SiteMap analysis, with site scores ranging from 0.549 to 0.943. Grid generation and docking were both performed on the top binding site, which had a site score of 0.943. This site corresponds to the highly conserved substrate-binding pocket in coronaviruses. The molecular docking was carried out using the Glide Xtra-Precision (XP) module, which use the E-model scoring function, in combination with the anchor-and-grow method for sampling, to select between protein–ligand complexes of a given ligand and the GlideScore [34]. The generalized born and surface area continuum solvation (MM-GBSA) module and the molecular mechanics energies were also used to perform binding-free-energy calculations on the XP-docked structures [31]. We shortlisted 50 potential drugs from the FDA-approved library based upon both XP docking energy and MM-GBSA scores (Table 1). Molecular docking of >2200 FDA-approved drugs at the similar hydrophobic core resulted in more than 50 potential drug molecules having a docking score of Table 1). The docking and MM-GBSA scores imply that these drugs may interact favorably, which might possibly inhibit Mpro activity. Figure 3 displays the top docking pose and ligand–protein interactions for the top 12 hits.The lowest docking score and MM-GBSA-based binding energy of −9.93 Kcal/mol and −77.27 Kcal/mol, respectively, were observed for iopamidol. Iopamidol interacts with the substrate-binding site by forming hydrogen bonds with Leu141, His164, Glu166, Gln189, and Thr190 and several nonbonded interactions. Iopamidol is a radiopaque contrast agent that contains iodine and is used for imaging of organs, blood vessels, and other tissues on a CT scan or other radiologic (X-ray) examination [35]. Like iopamidol, another radiocontrast agent, metrizamide, was also among the top drugs in our list [36,37]. Another top molecule in our list was mitoxantrone, having a docking score of −8.3 Kcal/mol and an MM-GBSA score of −69.9 Kcal/mol. Binding of mitoxantrone is mediated by several nonbonded interactions and a network of hydrogen bonds with Glu166, Thr190, and Gln189. Mitoxantrone is an immune suppressor and anticancer agent used for treating multiple sclerosis and cancer [38,39,40]. Interestingly, this drug has also been reported as a potential Mpro binder by Zhang et al. [41].Lumefantrine, with a docking score of −5.136 Kcal/mol and an MM-GBSA score of –66.8 Kcal/mol, is at the third position in our list. It binds Mpro with several nonbonded interactions, forms a hydrogen bond with Glu166, and has a π–π interaction with His41. Lumefantrine is an antimalarial agent used in treating acute uncomplicated malaria [42]. The next drug in our list is dipyridamole, which is a phosphodiesterase-2 inhibitor that blocks the metabolism and uptake of adenosine by erythrocytes and vascular endothelial cells [43]. It causes blood vessel dilation and inhibits blood clot formation and is used as a coronary vasodilator [43]. Docking analysis suggested that dipyridamole forms both hydrophobic and hydrophilic interactions with Mpro and interacts with Tyr54, Asn142, and Leu141 through hydrogen bonding, and its docking and MM-GBSA scores are −7.2 Kcal/mol and −65.56 Kcal/mol, respectively. Acebutolol is another potential drug that showed favorable binding in our docking studies, having a docking score of −7.3 Kcal/mol and an MM-GBSA score of −61.42 Kcal/mol. Docking analysis suggested that acebutolol is stabilized by hydrophobic interactions and hydrogen bonding with Asn142, His164, Glu166, and Gln189 residues in the Mpro binding pocket. Acebutolol is a cardio-selective, β-adrenoreceptor blocking agent. Acebutolol is used for treating high blood pressure, and it reduces an irregular heartbeat [44]. Ospemifene is a nonhormonal estrogen-receptor modulator that is used for the treatment of dyspareunia [45,46]. This drug also forms hydrophobic interactions and hydrogen bonding and interacts with Thr190 in the binding pocket, with −6.6 Kcal/mol docking and −60.68 Kcal/mol MM-GBSA scores. The next drug in this list is dihydroergotamine, a derivative of ergotamine and mainly used for the treatment of acute migraine. It docks with a binding score of −6.3 Kcal/mol and an MM-GBSA score of −60.62 Kcal/mol. Besides hydrophobic interactions, it forms hydrogen bonds with His 41, Thr190, and Asn142. Dihydroergotamine can be administered as a nasal spray; therefore, it can potentially be effective against pulmonary indications of COVID-19 infection [47]. Neratinib and palbociclib are two other anticancer drugs that appeared in our list which are used to treat early-stage HER2-positive or HER2-negative breast cancer patients, respectively [48,49]. Neratinib is known to limit the development of cancer cells by blocking their tyrosine kinase. It forms a hydrogen bond with Cys145, Cys189, Gly143, and Glu 166 residue with Mpro protein, and its docking and MM-GBSA scores are −6.56 Kcal/mol and −59.57 Kcal/mol, respectively. Another effective drug in our top-ten list is palbociclib. It is a cancer-preventive drug that inhibits cyclin-dependent kinases. It forms a hydrogen bond with Gln189, Glu 166, and Gly 143 residue with Mpro protein, and its docking and MM-GBSA scores are −6.29 Kcal/mol and −59.51 Kcal/mol, respectively.Hexoprenaline, which functions as a bronchodilator and an antiasthmatic and tocolytic agent by stimulating β-2 adrenergic receptors, is among the top-10 compounds in the list [50]. Besides several nonbonded interactions, hexoprenaline forms hydrogen bonds with Phe140, Glu166, and Thr190. Its binding and MM-GBSA scores are −6.35 and −58.35, respectively.Interestingly, in our docking studies, we also found two water-soluble vitamins, Riboflavin and Pantethine (derivative of vitamin B5), to be potential binders of Mpro. Riboflavin (Vitamin B2) is at the fifteenth position in our list. It binds with docking and MM-GBSA scores of −7.29 Kcal/mol and −53.66 Kcal/mol, respectively. It forms a hydrogen bond with Leu141, Gly143, and Glu166 in addition to having several nonbonded interactions. Pantethine appeared at the thirty-second position in the list, and it is a dimeric form of pantetheine, which is produced from pantothenic acid by the addition of cysteamine. It works as a cholesterol-lowering drug. It binds with docking and MM-GBSA scores of −6.365 Kcal/mol and −40.82 Kcal/mol, respectively. It forms a hydrogen bond with Thr26, Ser46, and Gly143 residues. Both riboflavin and pantethine, though having relatively lower ranks based on docking and MM-GBSA scores, being the safest biomolecules among the list, can be taken forward to evaluate Mpro-inhibitory activities. The bioavailability, cell penetration, half-life, and safety profile make riboflavin and pantethine potential candidates to be screened as an inhibitor of Mpro (Figure 3).

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