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Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking.

ABSTRACT: The COVID-19 pandemic continues without specific treatment. In this study it is proposed compounds that can be developed as adjuvant / complementary drugs against COVID-19. Through a search for molecular docking, for the development of a new drug using pharmacological compounds targeting the b1 region in neuropilin-1 (NRP1), which is important for the interaction with the S1 region of the S-Protein of SARS-CoV-2, to slow down the infection process of this virus. A molecular docking was performed using almost 500,000 compounds targeted to interact in the region between amino acids (Thr316, Asp320, Ser346, Thr349, and Tyr353) in NRP1 to determine compounds able to hinder the interaction with the S1 region in the S-Protein. In this study, ten compounds are proposed as potential inhibitors between S1 region in the S-Protein of SARS-CoV-2 with the b1 region in NRP1, to develop a new adjuvant / complementary drug against COVID-19, and to hinder the interaction between SARS-CoV-2 and human cells, with a high probability to be safe in humans, validated by web servers for prediction of ADME and toxicity (PreADMET).

SUBMITTER: Vique-Sanchez JL

PROVIDER: S-EPMC7826060 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking.

Vique-Sánchez José Luis JL

Bioorganic & medicinal chemistry 20210123

The COVID-19 pandemic continues without specific treatment. In this study it is proposed compounds that can be developed as adjuvant / complementary drugs against COVID-19. Through a search for molecular docking, for the development of a new drug using pharmacological compounds targeting the b1 region in neuropilin-1 (NRP1), which is important for the interaction with the S1 region of the S-Protein of SARS-CoV-2, to slow down the infection process of this virus. A molecular docking was performed ...[more]

PMID: 33515918

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Project description:The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus's spike protein. The cleavage site facilitates the entry of the virus into human cells via cell-cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of - 7 kcal.mol-1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between - 189 and - 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19.Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-02056-1.

Project description:The coronavirus disease 2019 (COVID-19) pandemic has posed a threat to public health throughout the world since the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was discovered in late 2019. Since the beginning of the pandemic, scientists have done a tremendous amount of work in this area. However, among these studies, the investigation of the effect of newly synthesized compounds against coronavirus is rather weak. Examining the newly synthesized compounds with a computer-assisted molecular docking study provides quite an advantage in terms of the estimation and analysis of the biochemical activity and binding affinity of existing synthesized compounds against a biological target in a labor, time, and cost-saving way. In this study, the SNS pincer type 2,6-bis[[(4-methylphenyl)thio]methyl]pyridine ligand(L) (1) and its novel Pd(II) complexes ([Pd(κ2-L)(OAc)2]·3H2O (2) and [Pd(κ2-L)Cl2]·3H2O (3)) were synthesized and characterized by using FT-IR, UV-Vis, NMR, mass and elemental analysis techniques. The synthesized Pd complexes exhibited a square planar structure. The compounds were found to have non-electrolytic behavior. In the meantime, in silico investigations have defined and justified interaction processes between these molecules and Pd(II) at the atomic level. Furthermore, using molecular docking against target proteins of SARS-CoV-2, the efficiency of the SNS pincer type ligand and its Pd (II) complexes produced was studied and discussed for the first time. The experimental data has been supported and illuminated using computational visual methods and molecular docking, and the findings produced indicate compatibility. The binding energy values of the relevant compounds on the four protein model structures of SARS-CoV-2 (Main Protease, Papain-like protease, RdRp without RNA, and RdRp with RNA) are represented. Compound 2 ([Pd(κ2-L)(OAc)2]·3H2O) is the structure that exhibits the highest biochemical activity. According to all of the docking studies, Papain-like protease is the SARS-CoV-2 protein with which the three compounds exhibit mutual interaction. The compound 2 structure, in particular, is the most effective in terms of structural and interaction with the targets, as well as binding orientations.

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Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking.

Publications

Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking.

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