A molecular docking study of futalosine derivatives as potential SARS-CoV-2 3CLpro inhibitors

Globalna pandemija COVID-19, koju je uzrokovao patogen SARS-CoV-2, u više od 2 godine odnijela je 6 200 000 života te zarazila pola milijarde ljudi diljem svijeta. Unatoč naporima svjetskih zdravstvenih vlasti, broj umrlih od te bolesti i dalje se svakodnevno bilježi i to u peteroznamenkastim iznosima. U namjeri da se pandemija okonča, znanstvenici se intenzivno bave razvojem učinkovitog antivirusnog lijeka. SARS-CoV-2 3CL proteaza pokazala se privlačnom metom u razvoju prikladnog inhibitora posjedujući sličnosti s dobro istraženim 3CL proteazama drugih koronavirusa. S obzirom na to da igra ključnu ulogu u generiranju nestrukturnih proteina bitnih za virusnu replikaciju, smatra se jednim od najbitnijih enzima odgovornih za virulenciju SARS-CoV-2. U prijašnjim istraživanjima futalozin se istaknuo kao prikladni kandidat za razvoj inhibitora SARS-CoV-2 3CLpro, pokazujući značajan inhibitorni učinak, ali i dobre strukturne i ADMET karakteristike poželjne kod razvoja lijeka. Vodeći se navedenim saznanjima, u ovom istraživanju metodom molekulskog sidrenja ispitivao se inhibitorni učinak ukupno 374 molekula, dizajniranih po uzoru na futalozin te prilagođenih prirodi aminokiselinskih ostataka u aktivnom mjestu enzima. Rezultati istraživanja pokazuju da molekula F41.17 od svih ispitivanih molekula posjeduje najbolji inhibitorni učinak na SARS-CoV-2 3CLpro. Energija vezanja F41.17 iznosi ΔG = -8,7 kcal mol-1 što je za 1,3 kcal mol-1 niže u odnosu na energiju vezanja futalozina, a osim što tvori više interakcija s aminokiselinama u aktivnom mjestu enzima, pokazalo se da posjeduje jednake farmakokinetičke značajke kao i futalozin, ako ne i bolje. Sve navedene karakteristike molekule F41.17 čine ju kandidatom vrijednim razmatranja u daljnjem razvoju inhibitora SARS-CoV-2 3CLpro.The outbreak of the Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has claimed 6 200 000 lives and infected half billion people worldwide in more than two years. Despite the efforts of world's health authorities, number of deaths from this disease is still recorded in tens of thousands on a daily basis. In an effort to end the pandemic, scientists are working intensively to develop effective antiviral drugs. SARS-CoV-2 3CL protease has shown to bear similarities to well-researched 3CL proteases of other coronaviruses and presents an attractive target in the development of suitable protease inhibitors. Furthermore, 3CLpro is considered to be one of the most important enzymes responsible for SARS-CoV-2 virulence because it plays a key role in generating nonstructural proteins that are essential in viral replication. In previous studies, futalosine proved to be a potential candidate for development of SARS-CoV-2 3CLpro inhibitors, showing not only a significant inhibitory effect, but also good structural and ADMET characteristics that are preferable in drug development. Based on these findings, in this study the inhibitory effect of a total of 374 molecules was investigated by molecular docking. The molecules were designed on the model of futalosine and adapted to the nature of amino acid residues in the active site of the enzyme. The results of the study show that the F41.17 molecule has the best inhibitory effect on SARS-CoV-2 3CLpro among all 374 candidates. The binding energy to the active site of enzyme is ΔG = -8,7 kcal mol-1, which is 1,3 kcal mol-1 lower than the binding energy of futalosine. In addition, the F41.17 molecule has shown to make more interactions with amino acids in the active site of the enzyme and also has equal pharmacokinetic features as futalosine, if not better. All these characteristics of the F41.17 molecule make it a candidate worth considering in further development of the SARS-CoV-2 3CLpro inhibitors