Sivakumar Prasanth Kumar

St. Jude Children's Research Hospital

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Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes

Combinatorial Chemistry & High Throughput Screening (2018)

Sivakumar Prasanth Kumar Prakash C. Jha

Aim and Objective: Numerous caspase-3 drug discovery projects were found to have relied on single receptor as the template to recognize most promising small molecule candidates using docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, this study was undertaken to develop receptor- and ligand-pharmacophore models based on different conformational schemes. Material and Methods: A multi-pharmacophore modeling strategy is carried out based on three conformational schemes of pharmacophore hypothesis generation to screen caspase-3 inhibitors from database. The schemes include (i) flexible (conformations unrestricted or flexible during pharmacophore mapping), (ii) dock (conformations obtained using FlexX docking method) and (iii) crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of query ligands. The pharmacophore models developed using these conformational schemes were then used to identify probable caspase-3 inhibitors from ZINC database. Results: We noticed better sensitivity with good specificity measures returned by candidate pharmacophore hypotheses across each conformation type and recognized crucial pharmacophore features that enable caspase-3 binding. Pharmacophore modeling based on flexible conformational scheme indicated that the crystal structure 3KJF (AAAADH) is the best receptor structure to perform receptor-based pharmacophore screening of caspase-3 inhibitors. When multiple crystal structures were included, the hypothesis (HAAA) is more generalized. Superimposition of multiple co-crystal ligands from various caspase-3 PDB entries in crystallographic binding mode revealed similar hypothesis (HAAA). Further, FlexX-guided dock conformations of validation dataset showed that the crystal structure 1RE1 is the best-suited for dock-based pharmacophore models. Database screening using these pharmacophore hypotheses identified N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4- yl]benzohydrazide as the probable caspase-3 inhibitors. Conclusion: N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-yl]benzohydrazide may be tested for caspase-3 inhibition. We believe that potential caspase-3 inhibitors can be recognized efficiently by adapting multi-pharmacophore models in database screening.

DOCK

Docking (animal)

10.2174/1386207321666180102114917

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Citations (4)

Synthesis and biological evaluation of cationic fullerene quinazolinone conjugates and their binding mode with modeled Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase enzyme

Journal of Molecular Modeling (2013)

Manishkumar B. Patel Sivakumar Prasanth Kumar Nikunj N. Valand Yogesh T. Jasrai Shobhana K. Menon

Quinazolinone

Phosphoribosyltransferase

Hypoxanthine

Cationic polymerization

Conjugate

10.1007/s00894-013-1820-1

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Citations (19)

Evolutionary and Molecular Aspects of Indian Tomato Leaf Curl Virus Coat Protein

International Journal of Plant Genomics (2012)

Sivakumar Prasanth Kumar Saumya Patel Ravi G. Kapopara Yogesh T. Jasrai Himanshu A. Pandya

Tomato leaf curl disease (ToLCD) is manifested by yellowing of leaf lamina with upward leaf curl, leaf distortion, shrinking of the leaf surface, and stunted plant growth caused by tomato leaf curl virus (ToLCV). In the present study, using computational methods we explored the evolutionary and molecular prospects of viral coat protein derived from an isolate of Vadodara district, Gujarat (ToLCGV-[Vad]), India. We found that the amino acids in coat protein required for systemic infection, viral particle formation, and insect transmission to host cells were conserved amongst Indian strains. Phylogenetic studies on Indian ToLCV coat proteins showed evolutionary compatibility with other viral taxa. Modeling of coat protein revealed a topology similar to characteristic Geminate viral particle consisting of antiparallel β-barrel motif with N-terminus α-helix. The molecular interaction of coat protein with the viral DNA required for encapsidation and nuclear shuttling was investigated through sequence- and structure-based approaches. We further emphasized the role of loops in coat protein structure as molecular recognition interface.

Leaf curl

Alfalfa mosaic virus

10.1155/2012/417935

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Citations (18)

PharmRF: A machine‐learning scoring function to identify the best protein‐ligand complexes for structure‐based pharmacophore screening with high enrichments

Journal of Computational Chemistry (2022)

Sivakumar Prasanth Kumar Nandan Dixit Chirag Patel Rakesh Rawal Himanshu Pandya

Abstract Structure‐based pharmacophore models are often developed by selecting a single protein‐ligand complex with good resolution and better binding affinity data which prevents the analysis of other structures having a similar potential to act as better templates. PharmRF is a pharmacophore‐based scoring function for selecting the best crystal structures with the potential to attain high enrichment rates in pharmacophore‐based virtual screening prospectively. The PharmRF scoring function is trained and tested on the PDBbind v2018 protein‐ligand complex dataset and employs a random forest regressor to correlate protein pocket descriptors and ligand pharmacophoric elements with binding affinity. PharmRF score represents the calculated binding affinity which identifies high‐affinity ligands by thorough pruning of all the PDB entries available for a particular protein of interest with a high PharmRF score. Ligands with high PharmRF scores can provide a better basis for structure‐based pharmacophore enumerations with a better enrichment rate. Evaluated on 10 protein‐ligand systems of the DUD‐E dataset, PharmRF achieved superior performance (average success rate: 77.61%, median success rate: 87.16%) than Vina docking score (75.47%, 79.39%). PharmRF was further evaluated using the CASF‐2016 benchmark set yielding a moderate correlation of 0.591 with experimental binding affinity, similar in performance to 25 scoring functions tested on this dataset. Independent assessment of PharmRF on 8 protein‐ligand systems of LIT‐PCBA dataset exhibited average and median success rates of 57.55% and 74.72% with 4 targets attaining success rate > 90%. The PharmRF scoring model, scripts, and related resources can be accessed at https://github.com/Prasanth-Kumar87/PharmRF .

Protein ligand

Docking (animal)

Matthews correlation coefficient

10.1002/jcc.26840

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Citations (7)

Novel cationic fullerene derivatized s-triazine scaffolds as photoinduced DNA cleavage agents: design, synthesis, biological evaluation and computational investigation

RSC Advances (2013)

Manishkumar B. Patel Uma Harikrishnan Nikunj N. Valand Deval Mehta Kuldeep V. Joshi

A series of novel cationic fullerene (C60) derivatives, bearing substituted s-triazine moiety as a side arm, synthesized by using the 1,3 dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted s-triazine is reported. All the synthesized compounds were characterized by elemental analysis, FT-IR, 1H NMR, 13C NMR and ESI-MS. The compounds 7a, 7d, 7e and 7f cleaved the supercoiled pBR322 DNA into nicked form efficiently upon visible light irradiation in the presence of NADH. The photoinduced superoxide radical and hydroxyl radical generated may act as molecular species causing the DNA scission. Further, the interaction of synthesized molecules with pBR322 plasmid DNA was investigated using computational approaches.

Moiety

Triazine

Cationic polymerization

Bond cleavage

10.1039/c3ra40950c

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Citations (13)

PLHINT: A knowledge-driven computational approach based on the intermolecular H bond interactions at the protein-ligand interface from docking solutions

Journal of Molecular Graphics and Modelling (2017)

Sivakumar Prasanth Kumar

Docking (animal)

AutoDock

Protein–ligand docking

Protein ligand

10.1016/j.jmgm.2017.12.002

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Citations (13)

A Computational Approach towards the Understanding of Plasmodium falciparum Multidrug Resistance Protein 1

ISRN Bioinformatics (2013)

Saumya Patel Linz-Buoy George Sivakumar Prasanth Kumar Hyacinth Highland Yogesh T. Jasrai

The emergence of drug resistance in Plasmodium falciparum tremendously affected the chemotherapy worldwide while the intense distribution of chloroquine-resistant strains in most of the endemic areas added more complications in the treatment of malaria. The situation has even worsened by the lack of molecular mechanism to understand the resistance conferred by Plasmodia species. Recent studies have suggested the association of antimalarial resistance with P. falciparum multidrug resistance protein 1 (PfMDR1), an ATP-binding cassette (ABC) transporter and a homologue of human P-glycoprotein 1 (P-gp1). The present study deals about the development of PfMDR1 computational model and the model of substrate transport across PfMDR1 with insights derived from conformations relative to inward- and outward-facing topologies that switch on/off the transportation system. Comparison of ATP docked positions and its structural motif binding properties were found to be similar among other ATPases, and thereby contributes to NBD domains dimerization, a unique structural agreement noticed in Mus musculus Pgp and Escherichia coli MDR transporter homolog (MsbA). The interaction of leading antimalarials and phytochemicals within the active pocket of both wild-type and mutant-type PfMDR1 demonstrated the mode of binding and provided insights of less binding affinity thereby contributing to parasite’s resistance mechanism.

Multidrug Resistance-Associated Proteins

P-glycoprotein

10.1155/2013/437168

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Citations (7)

Design, Synthesis, Biological Evaluation, and Molecular Modeling of Coumarin–Piperazine Derivatives as Acetylcholinesterase Inhibitors

Archiv der Pharmazie (2013)

Rahul P. Modh Sivakumar Prasanth Kumar Yogesh T. Jasrai Kishor H. Chikhalia

Acetylcholinesterase (AChE) is an important drug target for the treatment of Alzheimer's disease. A novel series of coumarin–piperazine derivatives were synthesized and their potency to inhibit human AChE enzyme ( h AChE) was studied. All the final compounds were characterized by infrared, 1 H NMR, 13 C NMR, and elemental analysis. Docking experiments of the designed coumarin–piperazine derivatives were carried out in order to compare the theoretical and experimental binding affinities toward h AChE, to delineate the inhibitory mechanism. Subsequently, a structure–activity relationship (SAR) study using the molecular field method showed that the hydrophobic field and positive charge center conferred by the coumarin and piperazine moieties demonstrated an inhibitory mechanism. Among the compounds tested, 3f , 3j , and 3m were found to be the most potent inhibitors of h AChE.

Piperazine

Docking (animal)

Molecular model

Proton NMR

Lead compound

10.1002/ardp.201300242

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Citations (28)

Pharmacophore-similarity-based QSAR (PS-QSAR) for group-specific biological activity predictions

Figshare (2015)

Sivakumar Prasanth Kumar Yogesh T. Jasrai Himanshu Pandya Rakesh Rawal

Recent technological breakthroughs in medicinal chemistry arena had ameliorated the perspectives of quantitative structure–activity relationship (QSAR) methods. In this direction, we developed a group-based QSAR method based on pharmacophore-similarity concept which takes into account the 2D topological pharmacophoric descriptors and predicts the group-specific biological activities. This activity prediction may assist the contribution of certain pharmacophore features encoded by respective fragments toward activity improvement and/or detrimental effects. We termed this method as pharmacophore-similarity-based QSAR (PS-QSAR) and studied the activity contribution of fragments from 3-hydroxypyridinones derivatives possessing antimalarial activities.

Similarity (geometry)

10.6084/m9.figshare.861021

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Citations (0)

Pharmacophore-similarity-based QSAR (PS-QSAR) for group-specific biological activity predictions

Figshare (2015)

Sivakumar Prasanth Kumar Yogesh T. Jasrai Himanshu Pandya Rakesh Rawal

Similarity (geometry)

10.6084/m9.figshare.861021.v3

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Citations (1)