Molecular Docking Study of Novel Imidazo[2,1-b]-1,3,4 thiadiazole derivatives

 

Ramjith U.S.¹* and Shahin Muhammed²

¹Department of Pharmaceutical Chemistry, Crescent College of Pharmaceutical Sciences, Madayipara, Payangadi (R.S), Kannur, Kerala -670358.

²Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Pariyaram, Kannur.

*Corresponding Author E-mail: ramjithganesh143@gmail.com

 

The molecular docking studies were performed on imidazo[2,1-b]-1,3,4thiadiazole derivatives using HVR protein. The compounds RUS-06, RUS-05, RUS-02, RUS-01, and RUS-07 were found to show best docking scores towards HVR protein (HIV protease receptor) indicating that these compounds may be screened for in vivo anti-HIV activity. The results showed that amongst the tested compounds with RUS-06 [dock score -117.41 and hydrogen bond energy -2.12 KJ] chloro (-Cl) substitution at 4^th position of benzyl ring at 2^nd position of imidazo[2,1-b]-1,3,4thiadiazole ring   and nitro (-NO₂) substitution on 4^th position of the phenyl ring at 6^th position of imidazo[2,1-b]-1,3,4thiadiazole ring was  found to have the highest affinity for HVR protein. It is concluded that when R and R¹ substituent’s are electron withdrawing groups(-Cl,-NO₂) those compounds (RUS-06,RUS-05) were found to possess greater affinity for HVR protein compared to compounds (RUS-01,RUS-02)  which contain R/R¹ substituted with electron withdrawing groups(-NO₂,Cl).  The compounds (RUS-03, RUS-11, RUS-12) with R and R¹ substituted with electron releasing groups (-CH₃,-OCH₃) were found to have least affinity for HVR protein. Further studies are required to establish their exact mechanism of action.

 

Where, R= H, Cl, CH₃;   R¹= Cl, NO₂, CH₃

 

KEYWORDS: Imidazo[2,1-b]-1,3,4thiadiazole,Dock score, HVR protein, anti-HIV activity,Hydrogen bond energy.

 

 

INTRODUCTION:

Imidazo[2,1-b]-1,3,4thiadiazole

Imidazole^1-3 and thiadiazole^4-6  moieties are associated with diverse pharmaceutical applications owing to the –N-C=N and toxophoric –N=C-S- groupings respectively.

 

Due to their fusion to form the fused heterocycle, the possibilities of reducing harmful effects of cytotoxic agents on the immune system also appears to be very attractive.

 

Thiazole (sulfathiazole, cefixime), Imidazo[2,1-b]thiazole and their bioisosteric derivatives such as thiadiazole (acetazolamide), imidazo[2,1-b][1,3,4]thiadiazole are regarded as safer and better drug molecules that are found to possess diversified biological activities like anti- bacterial³, diuretic, antifungal and leishmanicidal².

 

Anti-tumor potential of 2-amino [1,3,4]thiadiazole skeleton was recognized in early 1950’s and subsequently its fusion with imidazo[2,1-b] ring  system  has resulted in compounds with antibacterial⁴, anticancer⁶, cardiotonic and cytotoxic activities⁷.

 

Since imidazothiadiazole derivatives are found to be more useful, they are further focused for recent research work in green chemistry⁸ which revolves around the design, development and implementation of chemical processes and products that reduce or eliminate hazardous substances in a way that is feasible and economically viable.

 

Imidazo[2,1-b][1,3,4]thiadiazoles have been found to posses antisecretory⁹, analgesic¹⁰, antipyretic¹⁰,diuretic¹⁰, cardiotonic¹⁰, herbicidal¹⁰, anti-inflammatory¹⁰, antileishmanial¹¹ activities in addition to their antibacterial¹² and antifungal¹³ activities.

 

The  new imidazo [2,1-b][1,3,4]-thiadiazole compounds such as 2-(2-Methylphenyl)-6-phenyl-imdidazo[2,1-b][1,3,4]thiadiazole, 2-(2-Acetoxyphenyl)-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazole,  2-(2-Methylphenyl)-5-methyl-6-phenyl-imidazo[2,1-b][1,3,4]-thiadiazole, 2-(2-Oxy-α-propionic-acid-ethyl-ester)-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazole, 2-α-Ethylphenyl-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazole are found to have use  solely alone or in definite composition as antithrombotic agents and thrombolytic agents¹⁴.

 

The purpose of this work is to dock molecules containing imidazo[2,1-b][1,3,4]thiadiazole nucleus to HVR protein so as to further screen molecules for anti-HIV activity. 

 

Molecular Docking

Molecular docking is a method to predict the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Computers and programs (software’s) are used to predict or simulate the possible reaction (and interactions) between two molecules based on their three dimensional structures. The need for a rapid search for small molecules that may bind to targets of   biological interest is of crucial importance in the drug discovery process. One way of achieving this is the in silico or virtual screening (VS) of large compound collections to identify a subset of compounds that contains relatively many hits against the target, compared to a random selection from the collection. The compounds that are virtually screened can be obtained from corporate or commercial compound collections, or from virtual compound libraries. If a three-dimensional (3D) structure or model of   the target is available, a commonly used   technique is structure-based virtual screening (SBVS). Here a so-called ‘docking program’ is used to place computer-generated representations of a small molecule into a target structure (e.g., the active site of an enzyme) in a variety of positions, conformations and orientations.

 

Each such docking mode is called a ‘pose’. In order to identify the energetically most favourable pose (also referred to as ‘pose prediction’), each pose is evaluated (‘scored’) based on its complementarity to the target in terms of shape and properties such as electrostatics. A good score for a given molecule indicates that it is potentially a good binder. This process is repeated for all molecules in the collection, which are subsequently rank-ordered by their scores (i.e., their predicted affinities). This rank-ordered list is then used to select for purchase, synthesize or biologically investigate only those compounds that are predicted to be the most active. Assuming that both the poses and the associated affinity scores have been predicted with reasonable accuracy, this selection will contain a relatively large proportion of active molecules, i.e., it will be ‘enriched’ with actives compared to a random selection¹⁵.

 

A typical docking diagram of Imidazo[2,1-b]-1,3,4-thiadiazole derivative RUS-01

 

MATERIALS AND METHODS:

Docking Study of Imidazo[2,1-b]-1,3,4thiadiazole Derivatives

Protein used for docking: 1HVR (HIV-1 protease)¹⁶

Software used: MVD2010.4.0.

 

 

Table: 1- Compound Code and Structure

Code	Structures
RUS-01
RUS-02
RUS-03
RUS-04
RUS-05
RUS-06
RUS-07
RUS-08
RUS-09
RUS-10
RUS-11
RUS-12

 

Table 2:- Dock Score & Hydrogen Bond Energy of Imidazo[2,1-b]-1,3,4thiadiazole derivatives

RUS-02

 

RUS-03

Fig 1: Docking diagrams of RUS-02,RUS-03

 

 

RUS-06(Best docked structure with highest dock score and hydrogen bond energy)

Fig 2: Docking diagram of RUS-04 and RUS-05

 

RUS-04

 

 

RUS-05

Fig 3: Docking diagrams of RUS-04,RUS-05

 

RUS-06

 

RUS-07

Fig 4: Docking diagrams of RUS-06,RUS-07

 

Fig 5: Docking diagrams of RUS-08

 

Fig 6: Docking diagram of RUS-09 and RUS-10

 

Fig 7: Docking diagram of RUS-11 and RUS-12

RESULTS AND DISCUSSION

The docking studies were performed on HVR protein (HIV-1 protease) and from the studies it was found that the compound RUS-06  [(dock score -117.41 and hydrogen bond energy -2.12 KJ)] was found to have the greatest affinity to HVR protein (HIV-1 protease) followed by RUS-05 [(dock score -116.20 and hydrogen bond energy -2.96 KJ)], RUS-02[(dock score -114.23 and hydrogen bond energy -4.02 KJ)], RUS-01[(dock score -111.16 and hydrogen bond energy -0.71 KJ)].The compounds RUS-04[( dock score -99.07 and hydrogen bond energy -7.17 KJ)] RUS-03[( dock score -89.44 and hydrogen bond energy -2.50 KJ)], showed moderate affinity towards HVR protein while the compounds  RUS-08 (dock score -71.43 and hydrogen bond energy -1.25 KJ), RUS-09[( dock score -66.06 and hydrogen bond energy 0 KJ),RUS-10 [( dock score -64.60 and hydrogen bond energy 0 KJ), RUS-12 [( dock score -62.71 and hydrogen bond energy -2.12 KJ),RUS-11 [( dock score -54.44 and hydrogen bond energy -2.98 KJ), showed least affinity towards HVR protein.

 

It is suggested that the compounds RUS-06, RUS-05, RUS-02, and RUS-01 may be screened for in vivo anti-HIV activity.

 

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Received on 16.03.2013          Modified on 01.04.2013

Accepted on 10.04.2013         © RJPT All right reserved