Combination of QSAR, molecular docking, molecular dynamic simulation and MM-PBSA: analogues of lopinavir and favipiravir as potential drug candidates against COVID-19

Abstract

Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (M pro) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of M pro and RdRp in vitro. Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (M pro) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of M pro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the M pro. Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards M pro. In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19.

Effectiveness and safety of favipiravir compared to supportive care in moderately to critically ill COVID-19 patients: a retrospective study with propensity score matching sensitivity analysis

“…Novel antiviral drugs with activity against COVID-19 are under investigation, and molecular-docking studies of existing antiviral agents (e.g. protease inhibitors and FPV) have demonstrated that modified antiviral analogues have high drug scores and similarities to parent drugs with improved drug properties 33 .…”

“…Novel antiviral drugs with activity against COVID-19 are under investigation, and molecular-docking studies of existing antiviral agents (e.g. protease inhibitors and FPV) have demonstrated that modified antiviral analogues have high drug scores and similarities to parent drugs with improved drug properties 33 . Treatment guidelines published by the National Institutes of Health (NIH) do not include FPV as a treatment option in patients with confirmed COVID-19 infection, possibly due to its lack of availability in the US 34 .…”

A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study

“…It has been used to treat SARS and MERS patients but without proven efficacy [ 4 ]. Although lopinavir and its analogues were subjected to many studies [ 92 – 95 ], in clinical trials lopinavir-ritonavir combination have not been proven to be effective for the treatment of severe cases of COVID-19 [ 30 ]. Zhang et al [ 84 ] demonstrated lopinavir inhibition potential against SARS-CoV-2 3CLpro in vitro, and by extrapolation to in vivo, they concluded that due to very low concentration of free, unbound to plasma proteins, lopinavir is not effective against SARS-CoV-2 in vivo.…”

“…Zhang et al [ 84 ] demonstrated lopinavir inhibition potential against SARS-CoV-2 3CLpro in vitro, and by extrapolation to in vivo, they concluded that due to very low concentration of free, unbound to plasma proteins, lopinavir is not effective against SARS-CoV-2 in vivo. Paritaprevir [ 31 , 32 , 73 , 96 ], favipiravir [ 34 , 92 ], atazanavir [ 97 – 99 ], ganciclovir [ 95 , 97 ], tipranavir [ 73 , 98 , 100 – 102 ], and bictegravir [ 32 ], were part of computational studies trying to repurpose existing drugs against COVID-19. Paritaprevir is a compound containing an acylsulfonamide moiety and is being used in treatment of hepatitis C. It is inhibiting viral NS3/4A serine protease, with Ser139, His57 and Asp81 constituting catalytic triad [ 103 , 104 ].…”

Drug repurposing for COVID-19: Approaches, challenges and promising candidates

“…Therein, the RdRP embedded within the RTC is responsible for the replication of RNA and transcription of sub-genomic RNA. Antivirals which inhibit the RdRP, such as favipiravir, galidesivir, tenofovir, sofobuvir and clevudine have been proposed as COVID-19 repurposing candidates ( Elfiky, 2020 ; Rafi et al, 2020 ; Sultana et al, 2020 ). On the other hand, antivirals inhibiting RNA replication, such as remdesivir and emtricitabine, have shown promising clinical trial outcomes ( Ayerdi et al, 2020 ; Daoud, Alabed, & Dahabiyeh, 2021 ).…”