scholarly journals Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

2020 ◽  
Author(s):  
chinmayee choudhury
Keyword(s):  
Binding Site ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Corona Virus ◽  
Main Protease ◽  
New Chemical Entities ◽  
Reference Ligand ◽  
Binding Cavity ◽  
Binding Pockets ◽  
Dynamics Simulations

<p></p><p>The recent pandemic of novel corona virus (nCoV) infections (COVID19) has put the world on serious alert. The main protease of nCov (nCov-MP) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the nCov-MP binding site. A huge library of 191678 fragments was screened against the binding cavity of nCov-MP and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET property filters and MM-GBSA binding free energy calculations to select 17 best molecules (named as MP-In1 to Mp-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with nCov-MP, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with nCov-MP. Fifteen molecules were found to form stable complexes with nCov-MP. These novel chemical entities designed specifically according to the pharmacophoric requirements of nCov-MP binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for nCov drug discovery. </p><br><p></p>

scholarly journals Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

2020 ◽  
Author(s):  
chinmayee choudhury
Keyword(s):  
Binding Site ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Corona Virus ◽  
Main Protease ◽  
New Chemical Entities ◽  
Reference Ligand ◽  
Binding Cavity ◽  
Binding Pockets ◽  
Dynamics Simulations

<p></p><p>The recent pandemic of novel corona virus (nCoV) infections (COVID19) has put the world on serious alert. The main protease of nCov (nCov-MP) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the nCov-MP binding site. A huge library of 191678 fragments was screened against the binding cavity of nCov-MP and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET property filters and MM-GBSA binding free energy calculations to select 17 best molecules (named as MP-In1 to Mp-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with nCov-MP, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with nCov-MP. Fifteen molecules were found to form stable complexes with nCov-MP. These novel chemical entities designed specifically according to the pharmacophoric requirements of nCov-MP binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for nCov drug discovery. </p><br><p></p>

Fragment Tailoring Strategy to Design of Chemical Entities as Potential Binders of Novel Corona Virus Main Protease

2020 ◽  
Author(s):  
chinmayee choudhury
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Rna Virus ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Virus Infections ◽  
Corona Virus ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Tract Infections

<p>The recent pandemic of novel corona virus infections (COVID19) has put the world on serious alert. This is caused by a recent form of a positive sense RNA virus (nCoV) of coronaviridae family which is known to cause respiratory tract infections in humans. Absence of any specific drugs, vaccines or treatment measures for this deadly virus warrants intense research to design new chemical entities in order to inhibit the viral replication in human cells. The main protease of nCov (nCov-MP) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target. The current study employs state of are computational methods to design new molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the nCov-MP binding site. A huge library of 191678 fragments was screened against the binding cavity of nCov-MP and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET property filters and MMGBSA binding free energy calculations to select 17 best molecules (named as MP-In1 to Mp-In17), which showed interactions with the key binding site residues as the reference ligand. Nine out of these 17 molecules with better MMGBSA binding free energy than the reference molecule, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with nCov-MP. Eight molecules were found to form stable complexes with nCov-MP. These molecules can be further evaluated as potential starting points for nCov drug discovery. </p>

scholarly journals Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chirag N. Patel ◽  
Siddhi P. Jani ◽  
Dharmesh G. Jaiswal ◽  
Sivakumar Prasanth Kumar ◽  
Naman Mangukia ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Public Health Care ◽  
Dynamic Simulations ◽  
Energy Calculations ◽  
Main Protease ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

AbstractNovel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

scholarly journals Elucidating Biophysical Basis of Binding of Inhibitors to SARS-CoV-2 Main Protease by Using Molecular Dynamics Simulations and Free Energy Calculations

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Rajarshi Roy ◽  
Nisha Amarnath Jonniya ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Van Der Waals ◽  
Antiviral Drug ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Main Protease ◽  
Dynamics Simulations

<div>The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly</div><div>worldwide, causing a global pandemic. In the absence of a vaccine or a suitable</div><div>chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this</div><div>deadly respiratory disease. In the present work, we have elucidated the mechanism of binding</div><div>of two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mpro</div><div>or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We</div><div>calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed</div><div>ΔGbind into various forces governing the complex formation using the Molecular</div><div>Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal</div><div>that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -</div><div>3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to</div><div>Z31792168 arises due to an increase in the favorable electrostatic and van der Waals</div><div>interactions between the inhibitor and 3CLpro. Further, we have identified important residues</div><div>controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free</div><div>energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral</div><div>drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared</div><div>to both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van der</div><div>Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On</div><div>the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic</div><div>and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our</div><div>study might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 main</div><div>protease. </div>

scholarly journals Elucidating Biophysical Basis of Binding of Inhibitors to SARS-CoV-2 Main Protease by Using Molecular Dynamics Simulations and Free Energy Calculations

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Rajarshi Roy ◽  
Nisha Amarnath Jonniya ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Van Der Waals ◽  
Antiviral Drug ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Main Protease ◽  
Dynamics Simulations

<div>The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly</div><div>worldwide, causing a global pandemic. In the absence of a vaccine or a suitable</div><div>chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this</div><div>deadly respiratory disease. In the present work, we have elucidated the mechanism of binding</div><div>of two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mpro</div><div>or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We</div><div>calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed</div><div>ΔGbind into various forces governing the complex formation using the Molecular</div><div>Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal</div><div>that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -</div><div>3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to</div><div>Z31792168 arises due to an increase in the favorable electrostatic and van der Waals</div><div>interactions between the inhibitor and 3CLpro. Further, we have identified important residues</div><div>controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free</div><div>energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral</div><div>drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared</div><div>to both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van der</div><div>Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On</div><div>the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic</div><div>and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our</div><div>study might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 main</div><div>protease. </div>

scholarly journals Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

2020 ◽  
Vol 26 (42) ◽  
pp. 7598-7622 ◽  
Author(s):  
Xiao Hu ◽  
Irene Maffucci ◽  
Alessandro Contini
Keyword(s):  
Drug Discovery ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Free Energy Calculations ◽  
Binding Energies ◽  
New Drugs ◽  
Water Molecules ◽  
Open Questions ◽  
Dynamics Simulations ◽  
Computational Drug Discovery

Background: The inclusion of direct effects mediated by water during the ligandreceptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. Objective: In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. Results: Here, we analyse the software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. Conclusions: Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon.

scholarly journals Structure of theMycobacterium tuberculosisd-Alanine:d-Alanine Ligase, a Target of the Antituberculosis Drug d-Cycloserine

2010 ◽  
Vol 55 (1) ◽  
pp. 291-301 ◽  
Author(s):  
John B. Bruning ◽  
Ana C. Murillo ◽  
Ofelia Chacon ◽  
Raúl G. Barletta ◽  
James C. Sacchettini
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Kinetic Studies ◽  
Structural Rearrangement ◽  
Peptidoglycan Biosynthesis ◽  
Binding Cavity ◽  
Binding Pockets ◽  
Loop Regions ◽  
Discrete Domains ◽  
Alanine Dipeptide

ABSTRACTd-Alanine:d-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of twod-alanine (d-Ala) molecules to form thed-alanyl:d-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development.d-Cycloserine (DCS), an analog ofd-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure ofMycobacterium tuberculosisDdl at a resolution of 2.1 Å. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. TheM. tuberculosisapo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide andd-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP andd-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed ford-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC50) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.

scholarly journals The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 91 ◽  
Author(s):  
Rafał Kurczab ◽  
Katarzyna Kucwaj-Brysz ◽  
Paweł Śliwa
Keyword(s):  
Molecular Docking ◽  
Hot Spots ◽  
Binding Free Energy ◽  
Halogen Bonding ◽  
Free Energy Calculations ◽  
Dynamic Simulations ◽  
Receptor Complexes ◽  
Molecular Core ◽  
D4 Receptor ◽  
Dynamics Simulations

Recently, a computational approach combining a structure–activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand–receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand–receptor complex by halogen bonding.

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