Molecular insights to the binding interactions of APNS containing HIV-protease inhibitors against SARS-CoV-2 M^pro: anin silicoapproach towards drug repurposing

Article

Author: Meher, Biswa Ranjan ; Dash, Jiban Jyoti ; Muya, Jules Tshishimbi ; Purohit, Priyanka

SARS-CoV-2 M^pro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 M^pro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M^pro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 M^pro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 M^pro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔG_Bind = -28.31 kcal/mol) due to an increased favorable van der Waals (ΔE_vdw) interactions and decreased solvation (ΔG_solv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (-6.85 kcal/mol), KNI-227 (-18.36 kcal/mol), KNI-272 (-15.69 kcal/mol) and KNI-1931 (-21.59 kcal/mol) against SARS-CoV-2 M^pro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M^pro drugs.Communicated by Ramaswamy H. Sarma.

01 Apr 1993·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine

Q2 · MEDICINE

Article

Author: Shirasaka, T ; Murakawa, Y ; Erickson, J ; Ford, H ; Hayashi, H ; Mimoto, T ; Nomizu, M ; Gulnik, S ; Takada, K ; Kageyama, S

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.

01 Jan 1992·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Kynostatin (KNI-227 and -272, highly potent anti-HIV agents: conformationally constrained tripeptide inhibitors of HIV protease containing allophenylnorstatine.

Q4 · MEDICINE

Article

Author: Enomoto, Hiroshi ; Mimoto, Tsutomu ; Hattori, Naoko ; Kisanuki, Sumitsugu ; Akaji, Kenichi ; Kiso, Yoshiaki ; Imai, Junya

Selective and potent HIV protease inhibitors containing allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition-state mimic were designed and synthesized. Among them, conformationally constrained tripeptide derivatives, kynostatin (KNI)-227 and -272 (Fig. 1), exhibited highly potent antiviral activities against a wide spectrum of HIV isolates. Ready availability due to the simple synthetic procedure and the excellent antiviral properties indicate that KNI-227 and KNI-272 are promising candidates as selective anti-AIDS drugs.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Discovery	JP	Japan Energy, Inc.	-

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