The development of new drug candidates is really a very expensive process that consumes time and effort. Hence, there is an urgent need to develop new methods that are capable of predicting the important pharmacokinetic properties of drugs in a rapid and more accurate manner before being synthesized. Various computational models have emerged for the purpose of predicting ADMET (absorption, distribution, mechanism, excretion, and toxicity) parameters of drugs and drug-like compounds. This chapter focuses mainly on the characterization of the modern in silico techniques that predict the behavior of drugs during the early stages of drug discovery and development and the purposes, needs, and objectives of ADMET studies, which in turn facilitates the discovery of new drugs with more desired absorption, distribution, metabolism, and excretion profiles in addition to the least toxic effects. This chapter also provides an insight into the physicochemical parameters affecting the ADMET of drugs including the solubility, lipophilicity, permeability, as well as the hydrogen bonding. The in silico prediction of the active transport of drugs through various transporter types (P-gp, BCRP, nucleoside transporter, hPEPT1, hASBT, OCTs, OATPs, and BBB choline transporter) is also discussed. The recent in silico tools that are used in the modern ADMET software along with the future perspective and challenges are also covered.

Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties

Prostate cancer (PC) is one of the major impediments affecting men, which leads approximately 31,620 deaths in both developing and developed countries. Although some chemotherapy drugs have been re...

In silico approach of naringin as potent phosphatase and tensin homolog (PTEN) protein agonist against prostate cancer.

Synthesis, characterization and in-vitro anti-inflammatory activity of some substituted 1,2,3,4 tetrahydropyrimidine derivatives

A series of new fluorine containing pyrido[2,3-d]pyrimidines and imidazo[1,2-c]pyrido[3,2-e]pyrimidines along with a series of bioisosteric fluorinated quinazolines were synthesised following appropriate synthetic schemes and characterised by spectral analytical means. X-ray crystal structure of the key precursor 1 (2-amino-3-cyano-4-trifluoro-methyl-6-phenyl-pyridine) was also determined to gain insight into its reactivity. Binding affinity data of all the compounds for adenosine receptors (ARs) showed that pyrido[2,3-d]pyrimidine scaffold with free amino (NH2) group at 2- and 4-position (2a) exhibited the maximum binding affinity for hA3 AR with similar affinity for the hA1 and somewhat lower affinity for hA2A ARs resulting in a compound with no A3 selectivity vs. A1 and moderate selectivity vs. A2A AR (K
 i hA1 = 0.62 µM, hA2A = 3.59 µM and hA3 = 0.42 µM). Interestingly, the replacement of both the amino groups with carbonyl (C=O) groups (compound 4) resulted in significantly improved affinity for hA1 AR but with moderate selectivity against hA2A and hA3 ARs (K
 i hA1 = 0.17 µM, hA2A = 0.67 µM and hA3 = 0.68 µM). In case of fluorinated quinazolines, only compound 18a showed remarkable affinity for hA1 AR with significant selectivity against hA2A and hA3 ARs (K
 i hA1 = 0.73 µM, hA2A > 30 µM and hA3 = 9.27 µM). The preliminary results of these compounds demonstrate that the fluorinated pyrido[2,3-d]pyrimidine and imidazo[1,2-c]pyrido[3,2-e]pyrimidine can be considered as promising scaffolds for further optimisation in search of potential antagonists with better affinity and selectivity towards hA1 and hA3 ARs.

Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido[2,3- d ]pyrimidines and quinazolines

A series of novel 7-amino-5-oxo-2-substituted-aryl/hetero-aryl-5,8-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitriles (4a-4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA1 , hA2A , hA2B and hA3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2-position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA1 AR (Ki hA1  = 0.076 μM, hA2A  = 25.6 μM and hA3  > 100 μM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4-hydroxyphenyl group at 2-position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA1 AR of compound 4t (Ki hA1  = 0.051 μM, hA2A  = 9.01 μM and hA3  > 13.9 μM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2-position of the scaffold with π-excessive systems other than thiophene may lead to even more potent and selective hA1 AR antagonists.

7‐Amino‐2‐aryl/hetero‐aryl‐5‐oxo‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles: Synthesis and adenosine receptor binding studies

A series of new 4H-pyrimido(2,1-b)benzothiazole-2-arylamino-3-cyano-4-ones 6a-g have been designed and synthesized by the application of microwave-assisted organic synthesis (MAOS) technique. In silico docking studies have been carried out to gain an insight into the hypothetical binding motif of the title compounds using a homology model of A2B adenosine receptor employing GOLD (CCDC, 4.0.1 version) software. The binding modes are proposed on the basis of molecular docking studies.

http://nopr.niscair.res.in/bitstream/123456789/14508/1/IJCB%2051B%288%29%201105-1113.pdf

Design, microwave-assisted synthesis and in silico docking studies of new 4H-pyrimido(2,1-b)benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine A2B receptor antagonists

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Design, microwave-assisted synthesis and in silico docking studies of new 4H-pyrimido(2,1-b)benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine A2B receptor antagonists