A facile and single pot strategy for the synthesis of novel naphthyridine derivatives under microwave irradiation conditions using ZnCl2 as catalyst, evaluation of AChE inhibitory activity, and molecular modeling studies

Kurumurthy, C.; Rao, P. Shanthan; Veeraswamy, B.; Kumar, Gopinatha Suresh; Rao, P. Srinivasa; Kotamraju, Srigiridhar; Vasamsetti, Sathish Babu; Choudhury, Chinmayee; Narsaiah, B.

doi:10.1007/s00044-011-9695-0

Cited by 11 publications

(9 citation statements)

References 19 publications

(14 reference statements)

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“…In the last few decades, there has been rapid development in computational drug discovery algorithms for ab initio protein modeling, homology modeling, protein folding dynamics, molecular docking, pharmacophore modeling, virtual screening, quantitative structure activity relationship (QSAR) etc. (Choudhury et al, 2014) (Choudhury et al, 2015) (Choudhury et al, 2016) (Choudhury et al, 2016) (Gaur et al, 2017) (Kumar Srivastava et al, 2012) (Kurumurthy et al, 2012). Several new strategies are also designed for repurposing existing drugs or discover new ones (Passi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

Bhardwaj

Choudhury

2020

Preprint

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The current study examines the efficacy of dynamics-based hybrid pharmacophore models (DHPM) based on newly explored interaction features, as tools to screen potential inhibitors of Mycobacterium tuberculosis (Mtb)-DapB, a validated target essential for L-Lysin biosynthesis. Molecular dynamics (MD) simulations were performed on Mtb-DapB models, generated from a reported crystal structure by linking the cofactor (NADH) and substrate mimetic inhibitor (2,6-PDC), thereby creating a hybrid molecule (HM). Comparative investigation of the dynamics of interactions made by NADH, 2,6-PDC and HM from the MD trajectories revealed a number of stable interactions between HM and the hinge region residues leading to significant alterations of the Mtb-DapB structure. These newly identified interactions, translated into DHPM may be utilized as Mtb-DapB specific screening filters and provide new insights for structure activity relationships. To validate the applicability of the DHPM, about 10 million compounds compiled from the publicly available chemical space were screened using the DHPM as well as conventional pharmacophore models (based on the NADH/2,6-PDC). Systematic analyses of structures, physicochemical/ADMET properties and molecular docking of the 387 and 982 compounds screened by the DHPM and conventional models respectively demonstrate the capabilities of DHPM to screen structurally diverse chemical entities with better druglike properties and higher target binding potentials. The study demonstrates application of DHPM to predict 8 highly active anti-Mtb (MIC<=2µM)compounds whose mechanisms of action were previously unknown.3

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Section: Introductionmentioning

confidence: 99%

Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

Bhardwaj

Choudhury

2020

Preprint

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“…In the last few decades, structure-based inhibitor design has become very popular in preclinical drug development with the rapid advancements in the experimental techniques like X-ray crystallography or nuclear magnetic resonance, in silico tools and techniques as well as the computational power. More and more e cient algorithms are being implemented now a days for ab initio protein modeling, homology modeling, protein folding dynamics, molecular docking, pharmacophore modeling, virtual screening, quantitative structure activity relationship (QSAR) etc [7] [8] [9] [10] [11] [12] [13]. Several new strategies are also designed for repurposing existing drugs or nd new hits [14].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-tb Inhibitor Design: a Case Study With Mtb-dapb

Choudhury

Bhardwaj

2020

Preprint

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Antimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200ns molecular dynamics simulations and trajectories were analysed to identify stable ligand-receptor interaction features. Based on these interactions, Conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 15, 63,764 publically available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4 point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs and the reported anti-mycobacterial molecules indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

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“…Therefore, the trend is driving more towards fluorinated molecules. Keeping in view the importance of pyrido[2,3‐ d ]pyrimidines and in continuation of our efforts , we have synthesized a series of novel pyrido[2,3‐ d ]pyrimidine derivatives and screened them for anticancer activity against four human cancer cell lines. Compounds 7b , 7e , 7m , and 7o that showed high activity against all the four cancer cell lines have been identified.…”

Section: Introductionmentioning

confidence: 99%

Studies on Synthesis of Novel Pyrido[2,3‐d] pyrimidine Derivatives and Their Anticancer Activity

Veeraswamy

Jitender

Santhosh

et al. 2018

Journal of Heterocyclic Chem

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A facile and single pot strategy for the synthesis of novel naphthyridine derivatives under microwave irradiation conditions using ZnCl2 as catalyst, evaluation of AChE inhibitory activity, and molecular modeling studies

Cited by 11 publications

References 19 publications

Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-tb Inhibitor Design: a Case Study With Mtb-dapb

Studies on Synthesis of Novel Pyrido[2,3‐d] pyrimidine Derivatives and Their Anticancer Activity

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