De novo lead optimization of triazine derivatives identifies potent antimalarials.
TL;DR: A structure based drug discovery strategy for design of a series of effective and novel triazine based antimalarial drugs that showed low micro-molar activity against malarial parasite cell lines is reported.
Abstract: Malaria is a life-threatening disease caused by Plasmodium parasites among which Plasmodium falciparum is the most deadly. Due to the widespread resistance of the current antimalarial drugs, intense research efforts are focused on identification of new and potent antimalarials. We report here, a structure based drug discovery strategy for design of a series of effective and novel triazine based antimalarials. The X-ray structure of P. falciparum methyl transferase (PfPMT) is used as a target as it is unique to the parasite. The triazine molecules designed and synthesized showed low micro-molar activity against malarial parasite cell lines. Molecular dynamics simulations on the PfPMT-inhibitor complex shed light on the inhibition mechanism for further optimization of the lead compounds.
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TL;DR: The present review explored the current progress in the development of new promising antimalarials against prominent target proteins that have the potential to be a clinical candidate and highlighted new drug candidates that are currently in a clinical trial or clinical development.
18 citations
TL;DR: Triazine nucleus may be considered as interesting core moiety for researchers for the development of future drugs, as it has exposed potent pharmacological activity.
Abstract: Benzene is a six-membered hydrocarbon ring system and if three carbon-hydrogen units of benzene ring are replaced by nitrogen atoms then triazine is formed. Triazines are present in three isomeric forms 1,2,3- triazine, 1,2,4-triazine, and 1,3,5-triazine according to the position of the nitrogen atom. These are weak bases having weaker resonance energy than benzene, so nucleophilic substitution is preferred than electrophilic substitution. Triazine is an interesting class of heterocyclic compounds in medicinal chemistry. Numerous synthetic derivatives of triazine have been prepared and evaluated for a wide spectrum of biological activities in different models with desired findings such as antibacterial, antifungal, anti-cancer, antiviral, antimalarial, antiinflammatory, antiulcer, anticonvulsant, antimicrobial, insecticidal and herbicidal agents. Triazine analogs have exposed potent pharmacological activity. So, triazine nucleus may be considered as an interesting core moiety for researchers for the development of future drugs.
15 citations
TL;DR: In this article, 21 2,5-disubstituted 3-phenyl-1,2-dihydro derivatives have been synthesized and tested for their anticancer activity, and the selected compounds (13a, 13b, 13c, 13f, 13h, 13i, 13j, 18h, 18i, 21a4) were found to be active against different cancer cell lines.
Abstract:
Cancer is still an untreatable disease and the second leading cause of death
globally. The heterocyclic compounds have always played a major role in the anticancer drug discovery
program. 1,2,4-Triazine-6-ones is a heterocyclic privileged structure with diversified activities. In the
presented study, 21 novel 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6 (5H)-one derivatives
(13(a-k), 18(a-j) and 21(a1-a4, b)) have been synthesized and tested for their anticancer activity.
The 2,5-disubstituted-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one derivatives (13(a-k),
18(a-j) and 21(a1-a4, b) were synthesized by refluxing substituted-2-phenyloxazol-5(4H)-one and hydrazine
derivatives. Substituted aldehydes were synthesized via Vilsmeier-Haack reaction, while substituted-
2-phenyloxazol-5(4H)-one derivatives were synthesized by Erlenmeyer Plochl azlactone synthesis.
Twenty-one compounds were selected and screened at the National Cancer Institute (NCI), USA,
for anticancer activity at a single high dose (10-5M) in full NCI 60 cell panel assay.
The selected compounds (13a, 13b, 13c, 13f, 13h, 13i, 13j, 18h, 18i, 21a4)
were found to be active against different cancer cell lines. The compound, 5-((5-chloro-3-methyl-1-
phenyl-1H-pyrazol-4-yl)methylene)-2-(4-nitrobenzoyl)-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one
(13a) was found to be a potent anti-cancer agent as electron-rich moiety on phenyl at position 2 of triazine
nucleus, having a great impact on anticancer activity.
1 citations
TL;DR: In this article, a series of paraben substituted s-triazine compounds 1-5 were synthesized and their structures were determined by 1H and 13C NMR spectroscopies as well as mass spectrometry.
1 citations
01 Jan 2021
TL;DR: Sanjeevini as discussed by the authors is a comprehensive drug design software suite for lead molecule discovery taking off from protein and DNA as potential targets, which is a culmination of multiple modules of significance including detection of active sites in proteins and DNA in an automated manner, screening of a library of a million compounds for hit molecule identification, docking and scoring using all atom energy based algorithms and various other utilities which assist in designing hit molecules with desired affinities and specificities against the given targets.
Abstract: Sanjeevini, a comprehensive drug design software suite, has been developed for lead molecule discovery taking off from protein and DNA as potential targets. Sanjeevini is a culmination of multiple modules of significance including detection of active sites in proteins and DNA in an automated manner, screening of a library of a million compounds for hit molecule identification, docking and scoring using all atom energy based algorithms and various other utilities which assist in designing hit molecules with desired affinities and specificities against the given targets. A few of the modules of Sanjeevini software suite along with some of the success stories are illustrated in this chapter.
References
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TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
34,239 citations
TL;DR: In this article, the authors compared the Bernal Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P potential functions for liquid water in the NPT ensemble at 25°C and 1 atm.
Abstract: Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.
33,683 citations
TL;DR: In this paper, a method is described to realize coupling to an external bath with constant temperature or pressure with adjustable time constants for the coupling, which can be easily extendable to other variables and to gradients, and can be applied also to polyatomic molecules involving internal constraints.
Abstract: In molecular dynamics (MD) simulations the need often arises to maintain such parameters as temperature or pressure rather than energy and volume, or to impose gradients for studying transport properties in nonequilibrium MD A method is described to realize coupling to an external bath with constant temperature or pressure with adjustable time constants for the coupling The method is easily extendable to other variables and to gradients, and can be applied also to polyatomic molecules involving internal constraints The influence of coupling time constants on dynamical variables is evaluated A leap‐frog algorithm is presented for the general case involving constraints with coupling to both a constant temperature and a constant pressure bath
25,256 citations
TL;DR: In this paper, a numerical algorithm integrating the 3N Cartesian equations of motion of a system of N points subject to holonomic constraints is formulated, and the relations of constraint remain perfectly fulfilled at each step of the trajectory despite the approximate character of numerical integration.
18,394 citations
TL;DR: It is demonstrated that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N), which is comparable to that of a simple truncation method of 10 A or less.
Abstract: The previously developed particle mesh Ewald method is reformulated in terms of efficient B‐spline interpolation of the structure factors This reformulation allows a natural extension of the method to potentials of the form 1/rp with p≥1 Furthermore, efficient calculation of the virial tensor follows Use of B‐splines in place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy We demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N) For biomolecular systems with many thousands of atoms this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 A or less
17,897 citations