Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis.In an analysis of a randomly collected cohort of 124 patients with COVID-19,we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity.By virtual screening of a U.S.FDA approved drug library,we identified an anticoagulation agent dipyridamole(DIP)in silico,which suppressed SARS-CoV-2 replication in vitro.In a proof-of-concept trial involving 31 patients with COVID-19,DIP supplementation was associated with significantly decreased concentrations of D-dimers(P<0.05),increased lymphocyte and platelet recovery in the circulation,and markedly improved clinical outcomes in comparison to the control patients.In particular,all 8 of the DIP-treated severely ill patients showed remarkable improvement:7 patients(87.5%)achieved clinical cure and were discharged from the hospitals while the remaining 1 patient(12.5%)was in clinical remission.

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

Free energy perturbation(FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds,which is a topic of high interest in organic and medicinal chemistry.However,most approaches cannot efficiently predict the potency level of candidates after scaffold hopping.Herein,we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation(FEP)-guided scaffold-hopping strategy,and FEP shows great advantages to precisely predict the theoretical binding potenciesΔGFEPbetween ligands and their target,which were more consistent with the experimental binding potenciesΔGEXP(the mean absolute deviations|ΔGFEP-ΔGEXP|<2 kcal/mol)than thoseΔGMM-PBSAorΔGMM-GBSApredicted by the MM-PBSA or MM-GBSA method.Lead L12 had an IC_(50) of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil.Our work provides the first report via the FEPguided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold,implying that it will have a variety of future applications in rational molecular design and drug discovery.