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Article ; Online: Binding mode characterization of 13b in the monomeric and dimeric states of SARS-CoV-2 main protease using molecular dynamics simulations.

Kumari, Anita / Mittal, Lovika / Srivastava, Mitul / Asthana, Shailendra

Journal of biomolecular structure & dynamics

2021 Volume 40, Issue 19, Page(s) 9287–9305

Abstract: The main protease, ... ...

Abstract	The main protease, M
Language	English
Publishing date	2021-05-24
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2021.1927844
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Article ; Online: Harnessing the druggability at orthosteric and allosteric sites of PD-1 for small molecule discovery by an integrated in silico pipeline.

Mittal, Lovika / Tonk, Rajiv K / Awasthi, Amit / Asthana, Shailendra

Computational biology and chemistry

2023 Volume 107, Page(s) 107965

Abstract: The PD-1/PD-L1 interaction is a promising target for small molecule inhibitors in cancer immunotherapy, but targeting this interface has been challenging. While efforts have been made to identify compounds that target the orthosteric sites, no reports ... ...

Abstract	The PD-1/PD-L1 interaction is a promising target for small molecule inhibitors in cancer immunotherapy, but targeting this interface has been challenging. While efforts have been made to identify compounds that target the orthosteric sites, no reports have explored the potential of small molecules to target the allosteric region of PD-1. Therefore, our study aims to establish a pipeline to identify small molecules that can effectively bind to either the orthosteric or allosteric pockets of PD-1. We categorized the PD-1 interface into two hot-spot zones (P-and N-zones) based on extensive analysis of its structural, dynamical, and energetic properties. These zones correspond to the orthosteric and allosteric PPI sites, respectively, targeted by monoclonal antibodies. We used a guided virtual screening workflow to identify hits from ∼7 million compounds library, which were then clustered based on structural similarity and assessed by interaction fingerprinting. The selective and diverse chemical representatives were subjected to MD simulations and binding energetics calculations to filter out false positives and identify actual binders. Binding poses metadynamics calculations confirmed the stability of the final hits in the pocket. This study emphasizes the need for an integrated pipeline that uses molecular dynamics simulations and binding energetics to identify potential binders for the dynamic PD-1/PD-L1 interface, due to the lack of small molecule co-crystals. Only a few potential binders were discovered from a large pool of molecules targeting both the allosteric and orthosteric zones. Our results suggest that the allosteric site has more potential than the orthosteric site for inhibitor design. The identified "computational hits" hold potential as starting points for in vitro evaluations followed by hit-to-lead optimization. Overall, this study represents an effort to establish a computational pipeline for exploring and enriching both the allosteric and orthosteric sites of PPI interfaces, "a tough but indispensable nut to crack".
MeSH term(s)	Allosteric Site ; B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Molecular Dynamics Simulation ; Ligands ; Binding Sites ; Allosteric Regulation
Chemical Substances	B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Ligands
Language	English
Publishing date	2023-09-27
Publishing country	England
Document type	Journal Article
ISSN	1476-928X
ISSN (online)	1476-928X
DOI	10.1016/j.compbiolchem.2023.107965
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Article ; Online: Traversing through the Dynamic Protein-Protein Interaction Landscape and Conformational Plasticity of PD-1 for Small-Molecule Discovery.

Mittal, Lovika / Tonk, Rajiv / Awasthi, Amit / Asthana, Shailendra

Journal of medicinal chemistry

2022 Volume 65, Issue 8, Page(s) 5941–5953

Abstract: Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1 interface have shown remarkable success in treating malignancies, but they may also initiate lethal immune-related adverse events. Small molecules may circumvent the mAb limitations; however, none has ... ...

Abstract	Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1 interface have shown remarkable success in treating malignancies, but they may also initiate lethal immune-related adverse events. Small molecules may circumvent the mAb limitations; however, none has entered clinical trials targeting PD-1. Its complex protein-protein interaction interfaces necessitate an atomic-level understanding of recognition and binding mechanisms. Hence, we have aimed to highlight the PD-1's sequence-structure-dynamic-function link with its cognate ligands and diversely reported inhibitors. We focus primarily on the anti-PD-1 mAbs, their mode of actions, and interactions with PD-1 epitopes. The comparison of co-crystals showed that these ligands/inhibitors harness the PD-1's conformational plasticity and structural determinants differentially. The relationship between modulator binding patterns and biological activity is demonstrated using interaction fingerprinting of all reported human PD-1 co-crystals. The significant dynamical events and hot-spot residues underpinned from crystallographic wealth and computational studies have been highlighted to expedite small-molecule discovery.
MeSH term(s)	Animals ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents, Immunological/chemistry ; B7-H1 Antigen ; Humans ; Ligands ; Programmed Cell Death 1 Receptor/metabolism ; Protein Binding ; Protein Conformation
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; B7-H1 Antigen ; Ligands ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2022-04-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c00176
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Article ; Online: Deciphering the Structural Determinants Critical in Attaining the FXR Partial Agonism.

Kumari, Anita / Mittal, Lovika / Srivastava, Mitul / Pathak, Dharam Pal / Asthana, Shailendra

The journal of physical chemistry. B

2023 Volume 127, Issue 2, Page(s) 465–485

Abstract: Elucidation of structural determinants is pivotal for structure-based drug discovery. The Farnesoid X receptor (FXR) is a proven target for NASH; however, its full agonism causes certain clinical complications. Therefore, partial agonism (PA) appears as ... ...

Abstract	Elucidation of structural determinants is pivotal for structure-based drug discovery. The Farnesoid X receptor (FXR) is a proven target for NASH; however, its full agonism causes certain clinical complications. Therefore, partial agonism (PA) appears as a viable alternative for improved therapeutics. Since the agonist and PA both share the same binding site, i.e., ligand-binding pocket (LBP), which is highly dynamic and has synergy with the substrate binding site, the selective designing of PA is challenging. The identification of structural and conformational determinants is critical for PA compared with an agonist. Furthermore, the mechanism by which PA modulates the structural dynamics of FXR at the residue level, a prerequisite for PA designing, is still elusive. Here, by using ∼4.5 μs of MD simulations and residue-wise communication network analysis, we identified the structural regions which are flexible with PA but frozen with an agonist. Also, the network analysis identified the considerable changes between an agonist and PA in biologically essential zones of FXR such as helix H10/H11 and loop L:H11/H12, which lead to the modulation of synergy between LBP and the substrate binding site. Furthermore, the thermodynamic profiling suggested the methionine residues, mainly M
MeSH term(s)	Binding Sites ; Drug Discovery ; Ligands ; Protein Domains ; Receptors, Cytoplasmic and Nuclear/agonists
Chemical Substances	Ligands ; Receptors, Cytoplasmic and Nuclear ; farnesoid X-activated receptor (0C5V0MRU6P)
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.2c06325
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Article: Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp.

Srivastava, Mitul / Mittal, Lovika / Kumari, Anita / Asthana, Shailendra

Frontiers in molecular biosciences

2021 Volume 8, Page(s) 639614

Abstract: The COVID-19 pandemic has now strengthened its hold on human health and coronavirus' lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate ...

Abstract	The COVID-19 pandemic has now strengthened its hold on human health and coronavirus' lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate the discovery towards new therapeutics is an unmet need. Remdesivir (RDV) is established to inhibit RNA-dependent RNA polymerase (RdRp) in distinct viral families including Ebola and SARS-CoV-2. Therefore, its derivatives have the potential to become a broad-spectrum antiviral agent effective against many other RNA viruses. In this study, we performed comparative analysis of RDV, RMP (RDV monophosphate), and RTP (RDV triphosphate) to undermine the inhibition mechanism caused by RTP as it is a metabolically active form of RDV. The MD results indicated that RTP rearranges itself from its initial RMP-pose at the catalytic site towards NTP entry site, however, RMP stays at the catalytic site. The thermodynamic profiling and free-energy analysis revealed that a stable pose of RTP at NTP entrance site seems critical to modulate the inhibition as its binding strength improved more than its initial RMP-pose obtained from docking at the catalytic site. We found that RTP not only occupies the residues K545, R553, and R555, essential to escorting NTP towards the catalytic site, but also interacts with other residues D618, P620, K621, R624, K798, and R836 that contribute significantly to its stability. From the interaction fingerprinting it is revealed that the RTP interact with basic and conserved residues that are detrimental for the RdRp activity, therefore it possibly perturbed the catalytic site and blocked the NTP entrance site considerably. Overall, we are highlighting the RTP binding pose and key residues that render the SARS-CoV-2 RdRp inactive, paving crucial insights towards the discovery of potent inhibitors.
Language	English
Publishing date	2021-08-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2021.639614
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Article ; Online: Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp

Mitul Srivastava / Lovika Mittal / Anita Kumari / Shailendra Asthana

Frontiers in Molecular Biosciences, Vol

2021 Volume 8

Abstract: The COVID-19 pandemic has now strengthened its hold on human health and coronavirus’ lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate ...

Abstract	The COVID-19 pandemic has now strengthened its hold on human health and coronavirus’ lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate the discovery towards new therapeutics is an unmet need. Remdesivir (RDV) is established to inhibit RNA-dependent RNA polymerase (RdRp) in distinct viral families including Ebola and SARS-CoV-2. Therefore, its derivatives have the potential to become a broad-spectrum antiviral agent effective against many other RNA viruses. In this study, we performed comparative analysis of RDV, RMP (RDV monophosphate), and RTP (RDV triphosphate) to undermine the inhibition mechanism caused by RTP as it is a metabolically active form of RDV. The MD results indicated that RTP rearranges itself from its initial RMP-pose at the catalytic site towards NTP entry site, however, RMP stays at the catalytic site. The thermodynamic profiling and free-energy analysis revealed that a stable pose of RTP at NTP entrance site seems critical to modulate the inhibition as its binding strength improved more than its initial RMP-pose obtained from docking at the catalytic site. We found that RTP not only occupies the residues K545, R553, and R555, essential to escorting NTP towards the catalytic site, but also interacts with other residues D618, P620, K621, R624, K798, and R836 that contribute significantly to its stability. From the interaction fingerprinting it is revealed that the RTP interact with basic and conserved residues that are detrimental for the RdRp activity, therefore it possibly perturbed the catalytic site and blocked the NTP entrance site considerably. Overall, we are highlighting the RTP binding pose and key residues that render the SARS-CoV-2 RdRp inactive, paving crucial insights towards the discovery of potent inhibitors.
Keywords	SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) ; RDV triphosphate (RTP) ; molecular dynamics simulation ; PCA ; FEL ; NTP entrance site ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article: Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus.

Srivastava, Mitul / Mittal, Lovika / Sarmadhikari, Debapriyo / Singh, Vijay Kumar / Fais, Antonella / Kumar, Amit / Asthana, Shailendra

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 3

Abstract: The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for ... ...

Abstract	The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication; therefore, it is one of the primary targets for countermeasures against infectious diseases. The reported NNIs, belonging to the classes of quinolines (2h: imidazo[4,5-g]quinolines and 5m: pyrido[2,3-g] quinoxalines), displayed activity in cell-based and enzyme-based assays. Nevertheless, the RdRp binding site and microscopic mechanistic action are still elusive, and can be explored at a molecular level. Here, we employed a varied computational arsenal, including conventional and accelerated methods, to identify quinoline compounds' most likely binding sites. Our study revealed A392 and I261 as the mutations that can render RdRp resistant against quinoline compounds. In particular, for ligand 2h, mutation of A392E is the most probable mutation. The loop L1 and linker of the fingertip is recognized as a pivotal structural determinant for the stability and escape of quinoline compounds. Overall, this work demonstrates that the quinoline inhibitors bind at the template entrance channel, which is governed by conformational dynamics of interactions with loops and linker residues, and reveals structural and mechanistic insights into inhibition phenomena, for the discovery of improved antivirals.
Language	English
Publishing date	2023-03-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16030376
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Article ; Online: Characterizing (un)binding mechanism of USP7 inhibitors to unravel the cause of enhanced binding potencies at allosteric checkpoint.

Srivastava, Mitul / Mittal, Lovika / Kumari, Anita / Agrahari, Ashish Kumar / Singh, Mrityunjay / Mathur, Rajani / Asthana, Shailendra

Protein science : a publication of the Protein Society

2023 Volume 31, Issue 9, Page(s) e4398

Abstract: The ability to predict the intricate mechanistic behavior of ligands and associated structural determinants during protein-ligand (un)binding is of great practical importance in drug discovery. Ubiquitin specific protease-7 (USP7) is a newly emerging ... ...

Abstract	The ability to predict the intricate mechanistic behavior of ligands and associated structural determinants during protein-ligand (un)binding is of great practical importance in drug discovery. Ubiquitin specific protease-7 (USP7) is a newly emerging attractive cancer therapeutic target with bound allosteric inhibitors. However, none of the inhibitors have reached clinical trials, allowing opportunities to examine every aspect of allosteric modulation. The crystallographic insights reveal that these inhibitors have common properties such as chemical scaffolds, binding site and interaction fingerprinting. However, they still possess a broader range of binding potencies, ranging from 22 nM to 1,300 nM. Hence, it becomes more critical to decipher the structural determinants guiding the enhanced binding potency of the inhibitors. In this regard, we elucidated the atomic-level insights from both interacting partners, that is, protein-ligand perspective, and established the structure-activity link between USP7 inhibitors by using classical and advanced molecular dynamics simulations combined with linear interaction energy and molecular mechanics-Poisson Boltzmann surface area. We revealed the inhibitor potency differences by examining the contributions of chemical moieties and USP7 residues, the involvement of water-mediated interactions, and the thermodynamic landscape alterations. Additionally, the dissociation profiles aided in the establishment of a correlation between experimental potencies and structural determinants. Our study demonstrates the critical role of blocking loop 1 in allosteric inhibition and enhanced binding affinity. Comprehensively, our findings provide a constructive expansion of experimental outcomes and show the basis for varying binding potency using in-silico approaches. We expect this atomistic approach to be useful for effective drug design.
MeSH term(s)	Binding Sites ; Ligands ; Molecular Dynamics Simulation ; Protein Binding ; Protein Domains ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors
Chemical Substances	Ligands ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4398
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Template Entrance Channel as Possible Allosteric Inhibition and Resistance Site for Quinolines Tricyclic Derivatives in RNA Dependent RNA Polymerase of Bovine Viral Diarrhea Virus

Mitul Srivastava / Lovika Mittal / Debapriyo Sarmadhikari / Vijay Kumar Singh / Antonella Fais / Amit Kumar / Shailendra Asthana

Pharmaceuticals, Vol 16, Iss 376, p

2023 Volume 376

Abstract	The development of potent non-nucleoside inhibitors (NNIs) could be an alternate strategy to combating infectious bovine viral diarrhea virus (BVDV), other than the traditional vaccination. RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication; therefore, it is one of the primary targets for countermeasures against infectious diseases. The reported NNIs, belonging to the classes of quinolines (2h: imidazo[4,5-g]quinolines and 5m: pyrido[2,3-g] quinoxalines), displayed activity in cell-based and enzyme-based assays. Nevertheless, the RdRp binding site and microscopic mechanistic action are still elusive, and can be explored at a molecular level. Here, we employed a varied computational arsenal, including conventional and accelerated methods, to identify quinoline compounds’ most likely binding sites. Our study revealed A392 and I261 as the mutations that can render RdRp resistant against quinoline compounds. In particular, for ligand 2h, mutation of A392E is the most probable mutation. The loop L1 and linker of the fingertip is recognized as a pivotal structural determinant for the stability and escape of quinoline compounds. Overall, this work demonstrates that the quinoline inhibitors bind at the template entrance channel, which is governed by conformational dynamics of interactions with loops and linker residues, and reveals structural and mechanistic insights into inhibition phenomena, for the discovery of improved antivirals.
Keywords	bovine viral diarrhea virus (BVDV) ; RNA-dependent RNA polymerase (RdRp) ; BVDV inhibitor ; molecular dynamics simulations ; free energy calculations ; metadynamics ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	540
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Conformational Characterization of Linker Revealed the Mechanism of Cavity Formation by 227G in BVDV RDRP.

Mittal, Lovika / Srivastava, Mitul / Asthana, Shailendra

The journal of physical chemistry. B

2019 Volume 123, Issue 29, Page(s) 6150–6160

Abstract: RNA-dependent RNA polymerase (RdRp) is a relevant antiviral drug target. We investigated a potent benzimidazole inhibitor (227G; ... ...

Abstract	RNA-dependent RNA polymerase (RdRp) is a relevant antiviral drug target. We investigated a potent benzimidazole inhibitor (227G; IC
MeSH term(s)	Binding Sites ; Diarrhea Viruses, Bovine Viral/enzymology ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Movement ; Mutation ; Protein Conformation ; RNA Replicase/chemistry ; RNA Replicase/genetics ; RNA Replicase/metabolism
Chemical Substances	RNA Replicase (EC 2.7.7.48)
Language	English
Publishing date	2019-07-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.9b01859
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