Exploring the SARS-CoV-2 main protease (Mpro) and RdRp targets by updating current structure-based drug design utilizing co-crystals to combat COVID-19

2021 ◽  
Vol 22 ◽  
Author(s):  
Heena Tarannum ◽  
Rashmi KM ◽  
Sisir Nandi
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Economic Status ◽  
Genetic Material ◽  
Host Cells ◽  
Structure Based Drug Design ◽  
Genetic Components ◽  
Main Protease ◽  
Nmr Crystallography

: The unprecedented pandemic of COVID-19 caused by the novel strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engulfs millions of death worldwide. It has directly hit the socio-economic status of the affected countries. There are more than 219 countries badly affected by the COVID-19. There are no particular small molecule inhibitors to combat the dreadful virus. Many antivirals, antimalarials, antiparasitic, antibacterials, immunosuppressive anti-inflammatory, and immune stimulatory agents have been repurposed for the treatment of COVID19. But the exact mechanism of action of these drugs towards COVID-19 targets has not been experimented with yet. Under the effect of chemotherapeutics, the virus may change its genetic material and produces various strains, which are the main reasons behind the dreadful attack of COVID-19. The nuclear genetic components are composed of main protease and RNA-dependent RNA polymerase (RdRp) which are responsible for producing nascent virion and viral replication in the host cells. To explore the biochemical mechanisms of various small molecule inhibitors, structure-based drug design can be attempted utilizing NMR crystallography. The process identifies and validates the target protein involved in the disease pathogenesis by the binding of a chemical ligand at a well-defined pocket on the protein surface. In this way, the mode of binding of the ligands inside the target cavity can be predicted for the design of potent SARS-CoV-2 inhibitors.

scholarly journals Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939

2012 ◽  
Vol 68 (2) ◽  
pp. 115-118 ◽  
Author(s):  
Christina A. Kirby ◽  
Atwood Cheung ◽  
Aleem Fazal ◽  
Michael D. Shultz ◽  
Travis Stams
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Donor Site ◽  
Structure Based Drug Design ◽  
Crystallization System ◽  
Tankyrase 1

The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD+donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1–PJ34 crystallization system has the NAD+donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1–PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.

Structure-based Drug Design Strategies in the Development of Small Molecule Inhibitors Targeting Bcl-2 Family Proteins

2020 ◽  
Vol 17 (8) ◽  
pp. 943-953
Author(s):  
Zhe Yin ◽  
Donglin Yang ◽  
Jun Wang ◽  
Yuequan Jiang
Keyword(s):  
Clinical Trials ◽  
Drug Design ◽  
B Cell ◽  
Cancer Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Design Strategies ◽  
Structure Based Drug Design

Proteins of B-cell lymphoma (Bcl-2) family are key regulators of apoptosis and are involved in the pathogenesis of various cancers. Disrupting the interactions between the antiapoptotic and proapoptotic Bcl-2 members is an attractive strategy to reactivate the apoptosis of cancer cells. Structure-based drug design (SBDD) has been successfully applied to the discovery of small molecule inhibitors targeting Bcl-2 proteins in past decades. Up to now, many Bcl-2 inhibitors with different paralogue selectivity profiles have been developed and some were used in clinical trials. This review focused on the recent applications of SBDD strategies in the development of small molecule inhibitors targeting Bcl-2 family proteins.

Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design

2002 ◽  
Vol 45 (23) ◽  
pp. 5005-5022 ◽  
Author(s):  
Ingrid C. Choong ◽  
Willard Lew ◽  
Dennis Lee ◽  
Phuongly Pham ◽  
Matthew T. Burdett ◽  
...  
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Caspase 3 ◽  
Small Molecule Inhibitors ◽  
Structure Based Drug Design

Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies

2020 ◽  
Vol 19 (16) ◽  
pp. 1920-1934
Author(s):  
Xylia Q. Peters ◽  
Thembeka H. Malinga ◽  
Clement Agoni ◽  
Fisayo A. Olotu ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Design Methods ◽  
Selective Inhibitors ◽  
Computer Aided Drug Design ◽  
Cellular Processes ◽  
Conventional Drug ◽  
Computer Aided ◽  
Tankyrase 1

Background: Tankyrases are known for their multifunctionalities within the poly(ADPribose) polymerases family and playing vital roles in various cellular processes which include the regulation of tumour suppressors. Tankyrases, which exist in two isoforms; Tankyrase 1 and 2, are highly homologous and an integral part of the Wnt β -catenin pathway that becomes overly dysregulated when hijacked by pro-carcinogenic machineries. Methods: In this review, we cover the distinct roles of the Tankyrase isoforms and their involvement in the disease pathogenesis. Also, we provide updates on experimentally and computationally derived antagonists of Tankyrase whilst highlighting the precedence of integrative computer-aided drug design methods towards the discovery of selective inhibitors. Results: Despite the high prospects embedded in the therapeutic targeting and blockade of Tankyrase isoforms, the inability of small molecule inhibitors to achieve selective targeting has remained a major setback, even until date. This explains numerous incessant drug design efforts geared towards the development of highly selective inhibitors of the respective Tankyrase isoforms since they mediate distinct aberrancies in disease progression. Therefore, considering the setbacks of conventional drug design methods, can computer-aided approaches actually save the day? Conclusion: The implementation of computer-aided drug design techniques in Tankyrase research could help complement experimental methods and facilitate ligand/structure-based design and discovery of small molecule inhibitors with enhanced selectivity.

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

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