Molecular Docking in Modern Drug Discovery: Principles and Recent Applications

The process of hunt of a lead molecule is a long and a tedious process and one is often demoralized by the endless possibilities one has to search through. Fortunately, computational tools have come to the rescue and have undoubtedly played a pivotal role in rationalizing the path to drug discovery. Of all techniques, molecular docking has played a crucial role in computer aided drug design and has swiftly gained ranks to secure a valuable position in the modern scenario of structure-based drug design. In this chapter, the principle, sampling algorithms, scoring functions and diverse available software’s for molecular docking have been summarized. We demonstrate the interplay of docking, classical techniques of structure-based design and X-ray crystallography in the process of drug discovery. In addition, we dwell upon some of the limitations faced in docking studies. Finally, several success stories of molecular docking approaches in drug discovery have been highlighted, concluding with remarks on molecular docking for the future

Synthesis and In Vitro antiproliferative activity of 2-methyl-3-(2-piperazin-1-yl-ethyl)-pyrido1,2-apyrimidin-4-one derivatives against human cancer cell lines

A series of new 2-methyl-3-(2-piperazin-1-yl-ethyl)-pyrido1,2-apyrimidin-4-one derivatives 6a-j were synthesized by a nucleophilic substitution reaction of 2-methyl-3-(2-piperazin-1-ylethyl)-pyrido1,2-apyrimidin-4-one with various sulfonyl chlorides. The compounds were characterized by different spectral studies. All the compounds were evaluated for their antiproliferative effect using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method against four human cancer cell lines (K562, Colo-205, MDA-MB 231, IMR-32) for the time period of 24 h. Among the series, compounds 6d, 6e and 6i showed good activity on all cell lines except K562, whereas the other compounds in the series exhibited moderate activity. Compound 6d could be a potential anticancer agent and therefore deserves further research

Synthesis, anti-microbial activity and docking studies of 3-(2-(phenylamino)thiazol-4-yl)-2<i>H</i>-chromen-2-ones and ethyl 2-(2-(phenylamino)thiazol-4-yl)acetates

96-105Different approaches for the synthesis of a series of 3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-ones 5a-h is described. Also, 5a-h can be prepared by the reaction of salicylaldehyde with ethyl 2-(2-(phenylamino)thiazol-4-yl)acetates 6a-h which in turn are prepared by the reaction of ethyl 4-chloroacetoacetate with phenylthioureas. All the compounds 5a-h and intermediates 6a-h prepared in this work have been screened for their antimicrobial activities such as anti-bacterial and anti-fungal. Compounds 6e, 6g and 6h show good anti-bacterial activity. The molecular interaction of the synthesized compounds 6a-h with S. aureus FtsZ protein is supported by molecular docking studies

MEMES: Machine learning framework for Enhanced MolEcular Screening

In drug discovery applications, high throughput virtual screening exercises are routinely performed to determine an initial set of candidate molecules referred to as "hits". In such an experiment, each molecule from large small-molecule drug library is evaluated for physical property such as the docking score against a target receptor. In real-life drug discovery experiments, the drug libraries are extremely large but still a minor representation of the essentially infinite chemical space, and evaluation of physical property for each molecule in the library is not computationally feasible. In the current study, a novel Machine learning framework for Enhanced MolEcular Screening ("MEMES") based on Bayesian optimization is proposed for efficient sampling of chemical space. The proposed framework is demonstrated to identify 90% of top-1000 molecules from a molecular library of size about 100 million, while calculating the docking score only for about 6% of the complete library. We believe that such a framework would tremendously help to reduce the computational effort in not only drug-discovery but also areas that require such high-throughput experiments

Synthesis and Biological Evaluation of Imidazo[2,1-b]Thiazole based Sulfonyl Piperazines as Novel Carbonic Anhydrase II Inhibitors

A novel series of imidazo[2,1-b]thiazole-sulfonyl piperazine conjugates (9aa-ee) has been synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory potency against four isoforms: The cytosolic isozyme hCA I, II and trans-membrane tumor-associated isoform hCA IX and hCA XII, taking acetazolamide (AAZ) as standard drug, using a stopped flow CO2 hydrase assay. The results revealed that most of the compounds showed selective activity against hCA II whereas none of them were active against hCA I, IX, XII (Ki &gt; 100 &micro;M). The physiologically dominant cytosolic isoform hCA II was inhibited by these molecules with inhibition constants in the range of 57.7&ndash;98.2 &micro;M. This new derivative, thus, selectively inhibits hCA II over the hCA I, IX, XII isoforms, which may be used for further understanding the physiological roles of some of these isoforms in various pathologies

Molecular dynamic simulations reveal suboptimal binding of salbutamol in T164I variant of β2 adrenergic receptor.

The natural variant C491T (rs1800088) in ADRB2 gene substitutes Threonine to Isoleucine at 164th position in β2AR and results in receptor sequestration and altered binding of agonists. Present investigation pursues to identify the effect of T164I variation on function and structure of β2AR through systematic computational approaches. The study, in addition, addresses altered binding of salbutamol in T164I variant through molecular dynamic simulations. Methods involving changes in free energy, solvent accessibility surface area, root mean square deviations and analysis of binding cavity revealed structural perturbations in receptor to incur upon T164I substitution. For comprehensive understanding of receptor upon substitution, OPLS force field aided molecular dynamic simulations were performed for 10 ns. Simulations revealed massive structural departure for T164I β2AR variant from the native state along with considerably higher root mean square fluctuations of residues near the cavity. Affinity prediction by molecular docking showed two folds reduced affinity of salbutamol in T164I variant. To validate the credibility docking results, simulations for ligand-receptor complex were performed which demonstrated unstable salbutamol-T164I β2AR complex formation. Further, analysis of interactions in course of simulations revealed reduced ligand-receptor interactions of salbutamol in T164I variant. Taken together, studies herein provide structural rationales for suboptimal binding of salbutamol in T164I variant through integrated molecular modeling approaches

Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition

In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl ]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. (C) 2013 Elsevier Masson SAS. All rights reserved

Contact fractions of ligand-receptor interactions in course of simulation.

<p>Simulation interaction diagram showing contact fractions of residues interacting with salbutamol in (A) wild and (B) T164I variant of β2AR.</p

Structural perturbation incurred in β2AR upon T164I variation analyzed by simulations.

<p>(A) RMSD calculated for 10 ns of simulation trajectory for wild and T64I β2AR. β2AR is rendered with high conformational flexibility upon T164I substitution as observed from gradual rise in RMSD after 2.7 ns for T64I β2AR. (B) RMSF calculated for residues in wild and T164I variant. Purple bars indicate active site residues; arrow pointing the peak represents the site of variation. (C) Compactness of wild and T164I β2AR assessed by calculating radius of gyration. Trajectory lines for wild and T164I β2AR are represented in red and black color respectively.</p