In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

Abstract

The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆Ebinding between −5.1 and 7.1 kcal mol−1). The six compounds with the highest affinity show Kd between 6.26 × 10–6 and 17.2 × 10–6, with binding affinity between −20 and −25 kcal mol−1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 Mpro

“…21 Numerous investigations have thus been performed to characterize a potential inhibitor for the SARS-CoV-2 M pro . [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Several compounds have been suggested to be able to inhibit the biological activity of M pro . In this context, a compound, named PF-07321332, has emerged as one of the most potent candidates for an oral antiviral therapeutic factor.…”

Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations

“…68 Consequently, it is better than the docking energy of 26 inhibitors of SARS-CoV-2 Mpro (ranging from À5.1 to À7.2 kcal mol À1 ) mentioned in the recent work. 65 However, the obtained affinities were smaller than the top-lead compounds of Natural Product Arlats, which the docking energies adopted in the range from À8.2 to À9.4 kcal mol À1 . 69 Unbinding ligand to rene binding affinity AutoDock Vina uses numerous approximations such as acquired united-atom model, rigid receptor, and rarely tested ligand positions, the obtained results are thus required to rene via MD simulations.…”

Pharmacokinetics of Nafamostat, a Potent Serine Protease Inhibitor, by a Novel LC-MS/MS Analysis

“…Although the number of hydrogen bond donors is 7, nafamostat has the molecular weight (347.37) < 500, LogP (2.062) < 5, and hydrogen bond acceptors (7) < 10, satisfying Lipinski’s rule [ 29 ]. The topological polar surface area of 138 Å 2 and rotatable bond count of 5 also does not violate Veber’s rule for toxicity [ 30 ]. These predictions agree with the good safety profile of nafamostat and rapid absorption after oral administration.…”