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AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) SAR and Pharmacophore Based Designing of
Some Antimalarial and Antiretroviral Agents: An
INTERNET Based Drug Design Approach
Soumendranath Bhakat*
Department of Pharmaceutical Sciences
Birla Institute of Technology
Mesra, Ranchi-835215 INDIA
Received: April 26, 2012 Accepted: December 30. 2012 With the development of computational chemistry and molecular docking studies, Structure
Activity Relationship or SAR- and pharmacophore-based drug design have been modified to
target based drug discovery using sophisticated computational tools which is not very much user
friendly and has got many incompatibility issues with many operating systems (OS) and other
system configurations. In this paper SAR and pharmacophore based drug design approaches
have been described by the used of free internet based tools which are very much user friendly
and can almost compatible with any platform. Some antimalarial. And anti retroviral agents have
been designed using pharmacophore study and their drug like properties, toxicity, metabolic sites
and other parameters are predicted by the free internet based tools.

I.
rational drug design. These internet-based tools are easy to handle because they use In recent years computer-aided drug JAVA to input structure and calculate the [1-4] design has become an important tool drug likeness and molecular properties in for rational drug design on the basis of SAR real time. These JAVA based internet tools can be applied to predict the toxicity, pharmacophore study. The SAR and solubility, pKa, and Lipnski's five rule—all pharmacophore-based drug design [5-6] is important parameters for structure-based mainly based on Lipski's rule of five.[7] But rational drug design. the high cost of the necessary computational Recently structural analogue-based software, its lengthy and complicated drug discovery has become an important installation, and system compatibility issues tool for designing more potent drugs. This all make SAR-proficient software difficult for paper uses SAR, pharmacophore study, and general undergraduate students to handle. structural analogue-based novel drugs to Most of these software packages are design antimalarial anti-retroviral molecules using internet-based tools. WINDOWS versions (XP, 98, etc.) but are MATERIALS AND METHODS operating system, especially the 64 bit OS. SAR-proficient software requires compilation The structural analogue based drug and a lengthy installation procedure, and MOLSOFT, in which molecules' in-silico incompatibility issues with INTEL second drug likenesses and molecular property generation processors (i3, i5, i7, etc.). prediction tool are important.[8] The new To handle these difficulties in order molecules, designed on the basis of SAR to make drug design easier and convenient, and pharmacophore study, were then internet-based drug design on the basis of inputted into a JME molecular editor [9] to SAR and pharmacophores has become a allow different properties to be calculated. useful tool for modern structure-based The lazar toxicity of all these designed drugs have been performed using in-silico internet- * Email:[email protected] based lazar toxicity prediction tools.[10] The

AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Figure 1. Screenshot of OSIRIS Property Explorer.
Figure 2. Screenshot of MolSoft Drug likeness and Molecular Property prediction tool.
Figure 3. Screenshot of Lazar toxicity prediction tool.

AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13)
Figure 4. Screenshot of MetaPrint2D metabolic site prediction tool.

Figure 5. The 4-Amino quinolone pharmacophore, R1,R2 = positions of substitution.
OSIRIS Property Explorer [11] was also
kept malaria in check in most regions for used to predict toxicity and other drug-like decades. However, the rise in malaria properties. The metabolic sites of these deaths is due in part to the diseases' designed drugs have been predicted using increased resistance to chloroquine [14], MetaPrint2D. [12] All these calculations hence there is a necessity to design some were performed using a WINDOWS 7 64-bit more potent 4 aminoquinoline derivatives to operating system having Intel Core 2 duo introduce a more potent therapies. The first type of drug designed using internet based tools using chloroquine as Results and Discussions prototype drug having probable antimalarial activity as it consists of 4-aminoquinoline a. Designing of New Chloroquine structural analogues as probable antimalarial designed in such a way that it will show Inexpensive and stable antimalarial drugs such as the chloroquine [13] have AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Molecular properties* of AM1: Molecular formula: C19 H28 Cl N3 Molecular weight: 333.20 Number of HBA: 2 Number of HBD: 1 MolLogP : 5.90 (> 5) MolLogS : -5.71 (in Log(moles/L)) 0.65 (in mg/L) MolPSA : 24.58 A2 MolVol : 343.53 A3 Figure 6. Prototype molecule chloroquine
Number of stereo centers: 0 having MolSoft drug likeness score of 1.17 more drug likeness score than the prototype molecule pharmacophore essential for the antimalarial activity. The side chain present at 4 position of chloroquine have been modified with alteration of halogen atom in some cases at position 8 to get increased drug likeness score with the MolSoft Drug Likeness and Molecular Property prediction tool. In case of Drug likeness* score 1.25 designed molecules AM3, AM4 the chlorine molecule at position 8 have been replaced Molecular properties* of AM2: by –F atom to increase the MolSoft drug Molecular formula: C20 H30 Cl N3 likeness score than the prototype molecule Molecular weight: 347.21 Number of HBA: 2 chloroquine analogues with drug likeness Number of HBD: 1 MolLogP : 5.35 (> 5) molecular properties have been listed below. MolLogS : -5.89 (in Log(moles/L)) 0.44 (in The position of R1 and R2 in the 4- aminoquinolone ring (Figure 5) are modified MolPSA : 24.04 A2 in these designed molecules to get MolVol : 359.14 A3 increased drug likeness score. Number of stereo centers: 1 a. List of Designed Chloroquine Analogues with Molsoft Drug Likeness Scores and Predicted Molecular Properties properties, as predicted by MolSoft, are marked with an asterisk (*). Drug likeness* score 1.23 Molecule ID:AM3 Molecular properties* of AM3: Molecular formula: C19 H28 F N3 Molecular weight: 317.23 Number of HBA: 2 Number of HBD: 1 MolLogP : 5.27 (> 5) MolLogS : -5.13 (in Log(moles/L)) 2.37 (in Drug likeness* score 1.38 Molecule ID: AM1 AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Molecule ID
cLogP value
Solubility
Molecular
Likeness
Table 1. OSIRIS Property explorer values of designed chloroquine analogues. All parameters in
OSIRIS property explorer shows "green" colour for all designed drugs which indicates the drug
confirm behavior of these designed chloroquine analogues.
MolPSA : 24.58 A2
(NOR). A high NOR indicates a more MolVol : 332.26 A3 frequently reported site of metabolism in the Number of stereo centers: 0 occurrence ratio does not indicate how likely a molecule is to be metabolised, but rather the occurring at a particular site in the molecule, assuming it is metabolised. The Indication of colors which denotes predicted metabolic sites (see the Results Color Scheme on p. 39). On the basis of predicted lazar toxicity it is clear that the molecules AM3 Drug likeness score* 1.20 chloroquine,AM1 and AM2. But as the Molecule ID: AM4 toxicity level of the drugs AM1 and AM2 Molecular Properties* of AM4: have almost similar with chloroquine and in Molecular formula: C20 H30 F N3 some cases the confidence value for the Molecular weight: 331.24 predicted toxicity is more than that of Number of HBA: 2 chloroquine (the confidence value for the Number of HBD: 1 non-carcinogenic property of AM1 and AM2 in case of SingleCellCall** and Mouse** MolLogS : -5.31 (in Log(moles/L)) 1.61 (in parameters are more than that of the chloroquine) hence they are believed to be MolPSA : 24.04 A2 more potent than chloroquine as well. MolVol : 347.87 A3 Number of stereo centers: 1 0.66 <= NOR <= 1.00 b. Phase I Metabolic site prediction using MetaPrint2D by setting the strictness of 0.33 <= NOR < 0.66 the fingerprint matching in "DEFAULT" and selecting model "ALL 0.15 <= NOR < 0.33 0.00 <= NOR < 0.15 The color highlighting an atom indicates its normalized occurrence ratio Results Color Scheme AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Figure 7a. Predicted Phase I metabolic sites
Figure 7c. Predicted Phase I metabolic sites
Figure 7b. Predicted Phase I metabolic
Figure 7d. Predicted Phase I metabolic
AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) c Potency
Potency DBS
Potency DBS
Recommended
Potency DBS
c Potency
Daily Dose

Table 2. Predicted toxicity of chloroquine analogues using in-silico lazar toxicity prediction tool
http://lazar.in-silico.de/predict.
IV.
DESIGNED ARTEMISININ ANALOGUES AS ANTIMALARIAL Artemisinin [16] (Fig. 8) is a drug that posses the most rapid action of all falciparum malaria. To increase the potency (the main aim is to cure Artemisinin resistant malaria [17]) and make this drug more broad spectrum antimalarial agent the carbon at position 10 of Artemisinin is replaced by nitrogen with a side chain having a analogous chloroquine like side chain and a chlorine atom is attached with position 15 of Artemisinin. The new designed drug like molecules have been found to have more drug likeness score than that of the prototype drug Artemisinin (Artemisinin has a drug likeness score that of 1.22). The toxicity and metabolic sites of these designed drugs have been predicted using the toxicity, metabolic site prediction tools. Figure 8. The prototype drug Artemisinin.
AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) a. List of Designed Artemisinin Analogues with MolSoft Drug Likeness Scores and MolPSA : 55.19 A2 Predicted Molecular Properties MolVol : 443.65 A3 Number of stereo centers: 7 Molecule ID: AMM1 Drug-likeness score of AMM1: 1.97 Molecular Properties of AMM1: Molecule ID:AMM3 Molecular formula: C Drug likeness model score of AMM3:1.46 Molecular weight: 395.27 Molecular Properties of AMM3: Number of HBA: 6 Molecular formula: C21 H37 Cl N2 O4 Number of HBD: 0 Molecular weight: 416.24 MolLogP : 5.46 (> 5) Number of HBA: 6 MolLogS : -2.52 (in Log(moles/L)) 1202.47 Number of HBD: 0 MolPSA : 51.18 A2 MolLogS : -1.62 (in Log(moles/L)) 10018.30 MolVol : 445.00 A3 Number of stereo centers: 7 MolPSA : 42.77 A2 MolVol : 446.57 A3 Number of stereo centers: 8 Artemisinin and all its analogues have shown mutagenic, tumorigenic and irritant property as it shows in "red colour" in OSIRIS Property Explorer but all of their designed analogues have more drug score than that of Artemisinin hence it is predicted that these newly designed drug like molecules have much more potency than that of the prototype drug Artemisinin. b. Phase I Metabolic site prediction using MetaPrint2D by setting the strictness of the fingerprint matching in "DEFAULT" Molecule ID: AMM2 and selecting model "ALL (Metabolite Drug-likeness score of AMM2: 1.90 Molecular Properties of AMM2: Molecular formula: C21 H36 N2 O5 The color highlighting an atom Molecular weight: 396.26 indicates its normalized occurrence ratio Number of HBA: 7 (NOR). A high NOR indicates a more Number of HBD: 0 frequently reported site of metabolism in the MolLogS : -1.10 (in Log(moles/L)) 31431.52 occurrence ratio does not indicate how likely AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Molecule ID
cLogP value
Solubility
Molecular
Drug Score
Likeness
Prototype drug, Artemisinin
Table 3. OSIRIS Property explorer values of designed Artemisinin analogues.
Molecule
Potency DBS
Potency DBS
Potency DBS
ic Potency
ed Daily Dose
Table 4. Predicted toxicity of Artemisinin analogues using in-silico lazar toxicity prediction tool
http://lazar.in-silico.de/predict
a molecule is to be metabolised, but rather
c. Phase I Metabolic site prediction using MetaPrint2D by setting the strictness of occurring at a particular site in the molecule, the fingerprint matching in "DEFAULT" assuming it is metabolised. and selecting model "ALL (Metabolite All the designed drug like molecules taking the pharmacophore of lamivudine are found to have more drug score than that of The color highlighting an atom the prototype drug lamivudine which leads to indicates its normalized occurrence ratio confirm that all newly drug like molecules (NOR). A high NOR indicates a more might have increased and more potent frequently reported site of metabolism in the activity than that of lamivudine. occurrence ratio does not indicate how likely AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) a molecule is to be metabolised, but rather occurring at a particular site in the molecule, assuming it is metabolized. (See p. 39 for the Results Color Scheme.) Figure 8c. Predicted Phase I metabolic site
of AMM3.
All designed Artemisinin analogues have been predicted as non-carcinogen as well as non-mutagenic by the internet based lazar toxicity prediction tool this confirms that the rational and effective drug like molecules have been designed by SAR and pharmacophore study. V. DESIGN OF SOME LAMIVUDINE DERIVATIVES AS POTENT ANTI-RETROVIRAL AGENTS Lamivudine is a potent nucleoside analogue reverse transcriptase inhibitor [18]. Figure 8a. Predicted phase I metabolic site
To increase the potency of lamivudine as anti-HIV agent the –R part of lamivudine (Fig. 9) is substituted to get more potent designed increased drug likeness score in MolSoft drug likeness and property explorer tool. The prototype drug lamivudine has a drug likeness score of 1.05 and the designed drug like molecules have greater drug likeness score that of lamivudine Figure 8b. Predicted Phase I metabolic site
Figure 9. The pharmacophore of lamivudine.
AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Molecule ID
cLogP value
Solubility
Molecular
Drug Likeness
Drug Score

Table 5. OSIRIS Property explorer values of designed Lamivudine derivatives.
a. List of designed Lamivudine Analogues
with MolSoft Drug likeness Scores and Predicted Molecular Properties Drug-likeness score of LMA2: 1.23 Molecular Properties and Drug-likeness: Molecular formula: C10 H15 N3 O3 S Molecular weight: 257.08 Number of HBA: 5 Number of HBD: 1 Drug-likeness score of LMA1: 1.16 MolLogS : -1.81 (in Log(moles/L)) 3975.81 Molecular Properties of LMA1: Molecular formula: C10 H15 N3 O3 S MolPSA : 53.16 A2 Molecular weight: 257.08 MolVol : 259.27 A3 Number of HBA: 5 Number of stereo centers: 2 Number of HBD: 2 MolLogS : -2.12 (in Log(moles/L)) 1955.97 (in mg/L) MolPSA : 62.24 A2 MolVol : 256.18 A3 Number of stereo centers: 2 AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Figure 9a. Predicted Phase I metabolic site.
of LMA1
Molecule ID:LMA3 Drug-likeness score of LMA3: 1.30 Molecular Properties and Drug-likeness: Molecular formula: C11 H15 N3 O3 S Molecular weight: 269.08 Number of HBA: 5 Number of HBD: 2 MolLogP : 0.17 MolLogS : -2.15 (in Log(moles/L)) 1885.47 (in mg/L) MolPSA : 62.37 A2 MolVol : 272.08 A3 All the designed drug like molecules taking the pharmacophore of lamivudine are found to have more drug score than that of Figure 9b. Predicted Phase I metabolic site
the prototype drug lamivudine which leads to confirm that all newly drug like molecules might have increased and more potent activity than that of lamivudine. b. Phase I Metabolic Site Prediction using Metaprint2d by Setting the Strictness of the Fingerprint Matching in "DEFAULT" and Selecting Model "ALL (Metabolite 2010.2)" The color highlighting an atom indicates its normalized occurrence ratio (NOR). A high NOR indicates a more frequently reported site of metabolism in the metabolite occurrence ratio does not indicate how likely a molecule is to be metabolized, but rather the occurring at a particular site in the molecule, assuming it is metabolized. Figure 9c. Predicted Phase I metabolic site
AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) Molecule
c Potency
Potency DBS
Potency DBS
Potency DBS
Dose mmol

Table 6. Predicted toxicity of Artemisinin analogues using in-silico lazar toxicity prediction tool
http://lazar.in-silico.de/predict
From predicted lazar toxicity it is likeness, toxicity and other drug like and clear that the most effective design drug like molecular properties are easy to handle and molecule is LMA2 which posses lower user friendly. Designing of these drug like predicted toxicity level as compare with molecules by the pharmacophore study and prediction of drug like properties of these lamivudine. But all other design molecules molecules by the internet based tools hope will have be more effective than that of to speed up basic drug design research as lamivudine as LMA1 and LMA3 as both of all these tools are user friendly. Currently these drugs have lower predicted lazar work is going on the development of a toxicity than that of lamivudine (as compared "Miracle Molecule" by the use of internet by the "confidence" value generated by the based drug design tools which can be act as confidence value of predicted toxicity of anticancer, antibacterial agent as it will LMA1 and LMA3 than that of prototype drug contain all the pharmacophores necessary lamivudine suggests that they are less toxic for these activities and the work will be than lamivudine). reported in near future. ACKNOWLEDGEMENTS These entire designed drug like I am very much thankful to all my friends of molecules designed on the basis of SAR Birla Institute of Technology, Mesra, Ranchi- and pharmacophore study predicted to be 835215 for their healthy criticism and more effective and potent in nature than that constant encouragement. of all protype molecules. The predicted metabolic sites will be beneficial for computational chemists for docking analysis of these drugs and in choosing suitable 1. Marshall GR (1987) Computer-Aided targets. The internet based tools used in this study for calculating drug score, drug Pharmacology and Toxicology, Vol. 27: AMERICAN JOURNAL OF UNDERGRADUATE RESEARCH VOL. 11, NOS. 3 & 4 (2012-13) 193-213, DOI: 10.1146/annurev.pa. 27. Rev 46 pp 3–26. DOI:10.1016/S0169-
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