Computational elucidation of novel antagonists and binding insights by structural and functional analyses of serine hydroxymethyltransferase and interaction with inhibitors

Dikhit, Manas Ranjan; Ansari, Yousuf; Sinha, Sahil; Ali, Vahab; Topno, Roshan Kamal; Majhee, Jyoti Prava; Sahoo, Ganesh Chandra; Das, Pradeep

doi:10.1016/j.genrep.2017.10.010

Cited by 3 publications

(3 citation statements)

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“…The amino acid sequence of nonstructural polyprotein precursor glycoprotein of CHIKV (accession number: AQX78125.1) is obtained from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). The conserved domains were annotated by NCBI Conserved Domain Database (CDD) as described earlier . Notably, the amino acid residues between 1011 and 1675 consist of all four domains and selected for further analysis .…”

Section: Methodsmentioning

confidence: 99%

“…The conserved domains were annotated by NCBI Conserved Domain Database (CDD) as described earlier. [20][21][22] Notably, the amino acid residues between 1011 and 1675 consist of all four domains and selected for further analysis. 9,[23][24][25] The query sequence was then used to search the appropriate template in the protein data bank (PDB) To create a 3D coordinate file.…”

Section: Pdb Retrieval Sequence Alignment and Homology Modelingmentioning

confidence: 99%

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Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Kumar

Topno

Dikhit

et al. 2019

J of Cellular Biochemistry

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The arthropod‐transmitted chikungunya virus has emerged as an epidemic menace that causes debilitating polyarthritis. With this life‐threatening impact on humans, the possible treatment requires to cure the viral infectivity. But, devoid of any vaccine against the chikungunya virus (CHIKV), there is a need to develop a novel chemotherapeutic strategy to treat this noxious infection. CHIKV carries highly compact P23pro‐zbd structure that possesses potential RNA‐binding surface domains which extremely influences the use of RNA template during genome replication at the time of infection and pathogenesis. Therefore, computational approaches were used to explore the novel small molecule inhibitors targeting P23pro‐zbd domain. The tertiary structure was modeled and optimized using in silico approaches. The results obtained from PROCHECK (93.1% residues in favored regions), ERRAT (87.480 overall model quality) and ProSA (Z‐score: −11.72) revealed the reliability of the proposed model. Interestingly, a previously reported inhibitor, chloroquine possesses good binding affinities with the target domain. In‐depth analysis revealed that chloroquine derivatives such as didesethyl chloroquine hydroxyacetamide, cletoquine, hydroxychloroquine exhibited a better binding affinity. Notably, MD simulation analysis exhibited that Thr1312, Ala1355, Ala1356, Asn1357, Asp1364, Val1366, Cys1367, Ala1401, Gly1403, Ser1443, Tyr1444, Gly1445, Asn1459, and Thr1463 residues are the key amino acid responsible for stable ligand‐protein interaction. The results obtained from this study provide new insights and advances the understanding to develop a new approach to consider effective and novel drug against chikungunya. However, a detailed in vivo study is required to explore its drug likeliness against this life‐threatening disease.

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Section: Methodsmentioning

confidence: 99%

Section: Pdb Retrieval Sequence Alignment and Homology Modelingmentioning

confidence: 99%

Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Kumar

Topno

Dikhit

et al. 2019

J of Cellular Biochemistry

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“…Dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are the enzymes involved in the folate cycle and have gained a lot of attention as the prime targets for malaria and leishmania. Serine hydroxy methyltransferase (SHMT), which is also involved in the folate cycle, is now considered an important target for leishmania, bacterial, and protozoal diseases [ 1 ]. DHFR and TS are also prominent drug targets against different diseases such as various parasitic infections and cancer.…”

Section: Introductionmentioning

confidence: 99%

Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases

2022

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Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

et al. 2018

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Leishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania. In our previous study, we have deciphered the role of ISPs [LdISP1 and L. donovani inhibitor of serine peptidases 2 (LdISP2)] in the survival of L. donovani inside the sandfly midgut. However, the role of theses ISPs in the survival of L. donovani inside mammalian host still remains elusive. In the present study, we have deciphered the inhibitory effect of LdISPs on the host complement S1A serine peptidases, such as C1r/C1s and MASP1/MASP2. Our study suggested that although both rLdISP1 and rLdISP2 inferred strong interaction with C1complex and MBL-associated serine proteases (MASPs) but rLdISP2 showed the stronger inhibitory effect on MASP2 than rLdISP1. Moreover, we found that rLdISP2 significantly reduces the formation of C3, C5 convertase, and membrane attacking complex (MAC) by lectin pathway (LP) resulting in significant reduction in serum mediated lysis of the parasites. The role of LdISP2 on neutrophil elastase-mediated C5aR signaling was also evaluated. Notably, our results showed that infection of macrophages with ISP2-overexpressed Leishmania parasites significantly induces the expression of C5aR both at the transcript and translational level. Simultaneously, infection with ISP2KD parasites results in downregulation of host PI3K/AKT phosphorylation and increased in IL-12 production. Taken together, our findings clearly suggest that LdISP2 promotes parasite survival inside host by inhibiting MAC formation and complement-mediated lysis via LP and by upregulation of C5aR signaling.

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Computational elucidation of novel antagonists and binding insights by structural and functional analyses of serine hydroxymethyltransferase and interaction with inhibitors

Cited by 3 publications

References 57 publications

Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

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Computational elucidation of novel antagonists and binding insights by structural and functional analyses of serine hydroxymethyltransferase and interaction with inhibitors

Cited by 3 publications

References 57 publications

Molecular docking studies of chloroquine and its derivatives against P23pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Molecular docking studies of chloroquine and its derivatives against P23pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases

Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host

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Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies

Molecular docking studies of chloroquine and its derivatives against P23^pro‐zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies