Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug Design Approaches

Abstract

Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between −6.5 and −7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.

Most frequently harboured missense variants of hACE2 across different populations exhibit varying patterns of binding interaction with spike glycoproteins of emerging SARS-CoV-2 of different lineages

“…RMSD is a measurement of the average displacement of selected atoms in a particular timeframe with respect to a reference frame [ 46 ]. During the initialization of the simulation, the protein structures were aligned with the backbone frame, and the RMSD was calculated using Equation (2) .…”

Amazon Plant‐Derived Compounds Suppressing Dengue NS5 Protein: Insights from Computational Drug Development and Network Pharmacology Approach

“…The RMSD in MD simulations serves the average distances produced by removing one molecule from a system throughout a predetermined amount of duration in comparison to a reference value. [43] The RMSD of protein fit ligand atoms over every time frame, that is coordinated as well as assessed against the benchmark time, is added after the RMSD of protein structural atoms, including as C, foundation, sidechain, as well as bulkier elements (In our 100 ns MDS analysis). The following equation may be used to calculate the RMSD of an MD simulation using a period of x (Equation 1).…”

Natural resistance of tomato plants to Tomato yellow leaf curl virus

“…Strict quarantine laws, integrated pest management, and traditional breeding are only a few methods to stop the spread of TYLCV ( Prasad et al., 2020 ). TYLCV transmission is one of several recent transgenic strategies and traditional methods used to combat virus transmission ( Pramanik et al., 2021 ; Asseri et al., 2022 ). Tomato plants that express TYLCV gene segments, such as replication-associated protein (Rep) ( Antignus et al., 2004 ) or capsid protein (CP) provide resistance to the virus ( Yang et al., 2004 ).…”